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The nuclear pore complex (NPC) is an evolutionarily conserved structure that maintains the traffic between the nucleus and cytoplasm. Here, we profiled the expression of nucleoporins (NUPs) in glioblastoma stem cells (GSCs) and found that NUP98 promoted GSC maintenance and therapeutic resistance. GSCs preferentially expressed NUP98, which is essential for GSC tumorigenesis in vitro and in vivo. RNA sequencing demonstrated that NUP98 regulated the expression of key DNA damage and repair pathways. NUP98 formed a complex with transcription factor p65 to directly activate genes involved in homologous repair. Attenuation of NUP98 or p65 expression induced unrepaired intrinsic DNA damage and sensitized GSC to ionizing radiation. Clinically, overexpression of NUP98 informs poor clinical outcome among glioblastoma (GBM) patients. Collectively, our results demonstrate that NUP98-p65 represents a novel node in the regulation of DNA repair, suggesting a therapeutic strategy with potential clinical benefits for GBM patients., (© 2025 Federation of American Societies for Experimental Biology.)

Cell cycle arrest and programmed cell death are crucial biological processes in cancer development. Regulating cell fate decisions is essential due to their potential to induce cell cycle arrest and cell death. Inducing cell cycle regulatory proteins in tumor cells is considered a key objective in cancer therapy. Here, we present a novel method that selects antibodies from an antibody library to inhibit cancer growth using fluorescence-activated cell sorting (FACS) assays and cell cycle analysis. This approach seeks antibodies that induce cancer cells to enter the G0 or G1 phase, a quiescent state where cells cease to proliferate and trigger programmed cell death. We found that the T1 antibody effectively suppresses the proliferation of cancer cells. Mechanistically, serine protease 3 (PRSS3) is a target antigen of the T1 antibody. We demonstrated that PRSS3 controls tumor cell proliferation and apoptosis through interaction with the T1 antibody. This research suggests that PRSS3 holds great potential as a target for solid cancer treatment. This cycle-based approach to antibody screening shows potential because it can be broadly applied to cancer and other challenging diseases., (© 2025 Federation of American Societies for Experimental Biology.)

In recent years, there has been a gradual increase in the incidence and mortality rates of melanoma, posing a significant threat to human health and life. Protein tyrosine phosphatases (PTPNs) have been implicated in the progression of various human cancers, including breast, lung, and cervical cancer. To investigate PTPN9 expression in melanoma, impacting the disease's survival and prognosis. Our study, which involved an analysis of The Cancer Genome Atlas database and immunohistochemical staining of pathological sections, identified an upregulation of PTPN9 expression in melanoma, impacting the disease's survival and prognosis. At the cellular level, we investigated the effects of PTPN9 on the proliferation, invasion, and metastasis of A375 and SK-MEL-28 cells. Through various experimental techniques such as Western blot protein detection, electron microscopy, and oil red O staining, we observed that PTPN9 potentially contributes to the development of skin cutaneous melanoma (SKCM) by regulating ferroptosis-related proteins ACSL4, FTH1, and P53, thereby influencing lipid metabolism. The results of this study highlight the unique role of PTPN9 in SKCM and suggest its potential as a biomarker for the disease., (© 2025 Federation of American Societies for Experimental Biology.)

Black rice (BR) extract contains several functional food bioactive components that are health-promoting. This study assessed the multifunctional bioactivities of various BR extracts (methanol, ethanol, acetone, and aqueous). These BR extracts revealed significant antioxidant and antibacterial activity against various bacterial strains. Acetone extract exhibited high cytotoxicity against gastric adenocarcinoma cells (AGS), while ethanol extract was cytotoxic against pancreatic cancer cells (PANC-1). Moreover, the acetone extract induced 33.6 % and 16.5 % apoptosis in PANC-1 and AGS cells, respectively. Acetone extract showed significant anti-inflammatory action, reducing 76 % production of nitric oxide in the RAW 264.7 (murine macrophage). Furthermore, all BR extracts inhibited PANC-1 and AGS migration and promoted RAW 264.7 migration. Field emission scanning electron microscope, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis of the BR-polyhydroxybutyrate composite revealed successful deposition for BR extracts. This study highlights the potential of BR extracts to develop multifunctional activity-based strips for rapid wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Pseudostellaria heterophylla (Miq.) Pax (PH) is a traditional folk medicine, which is widely used clinically for digestive system tumors such as esophageal, gastric, colorectal, and liver cancers. The anti-tumor effect and mechanism of PH in colorectal cancer (CRC) deserves further study., Aim of the Study: The objective of this study is to examine the effects and the underlying mechanisms of aqueous extract of Pseudostellaria heterophylla (Miq.) Pax (AEPH) in the CRC., Materials and Methods: The components of AEPH were fully resolved using ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap high-resolution mass spectrometry (UHPLC-Q/Orbitrap HRMS). The effect of AEPH was evaluated in vivo using the MC38 mouse colon cancer model, and its impact on the tumor microenvironment was analyzed by flow cytometry. Bioinformatics analysis, combined with transcriptome sequencing, was utilized to further investigate the signaling pathways of AEPH in CRC cells., Results: A mass spectrometry analysis identified 371 compounds in AEPH, each with a comprehensive score exceeding 60. In vivo experiments demonstrated that AEPH suppressed the growth of MC38 tumors without exhibiting obvious toxicity. Mechanistic studies revealed that AEPH inhibited the JNK signaling pathway, reduced Chemokine C-C Motif Chemokine Ligand 5 (CCL5) secreted by CRC cells, hindered the recruitment of M2-like tumor-associated macrophages (TAMs), promoted the infiltration of IFN-γ + CD8 + T cells, and improved the immunosuppressive microenvironment of CRC., Conclusion: AEPH contributes to the remodeling of the tumor immune microenvironment primarily through the inhibition of CCL5-mediated recruitment of M2-like TAMs. The findings of this study offer a novel perspective on the potential development of AEPH as a therapeutic agent for CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, featuring a high proportion of cancer stem cells (CSCs) and the poorest clinical outcomes. Taraxacum mongolicum Hand. -Mazz., widely recognized as dandelion, is a traditional medicinal herb that has demonstrated promising anti-TNBC potential. However, the efficacy of dandelion in anti-TNBC stem-like properties remains to be elucidated., Aim of the Study: The aim was to examine the impact of dandelion extract on the stemness properties of TNBC and to delineate the underlying mechanisms., Materials and Methods: UHPLC-Q-Orbitrap HRMS was employed to characterize the components present in dandelion extract. Network pharmacology was utilized to explore the impact of dandelion-derived compounds on the molecular pathways associated with TNBC. The assessment of TNBC stem-like properties was conducted through mammosphere formation assays and flow cytometry analysis. Western blotting, qRT-PCR, and immunofluorescence were employed to investigate the mechanisms of dandelion extract. 4T1-luc xenograft tumor model was used to assess the anti-tumor effect of dandelion extract in vivo. IVIS imaging technology was used to monitor lung metastasis., Results: In this study, pharmacological network analysis revealed the potential regulatory effects of dandelion extract on TNBC stemness. Dandelion extract disrupts the stem-like properties in MDA-MB-231 and MDA-MB-468 cell lines via reducing ALDH + cells proportion, impeding mammosphere formation, and downregulating CSC-related markers, including SOX2, SOX9, NANOG, and FOXM1. Furthermore, CUE domain containing protein 2 (CUEDC2) promotes the maintenance of TNBC stemness and contributes to the anti-stemness effects of dandelion extract. Mechanistically, dandelion extract inhibits CUEDC2-mediated nuclear translocation of β-catenin, thereby reducing the transcriptional activity of OCT4. In vivo, dandelion extract suppresses tumor growth, lung metastasis, and decreases the expression of CSC-related markers., Conclusion: These findings suggest that dandelion extract inhibits TNBC stem-like properties via modulating the CUEDC2/β-catenin/OCT4 signaling axis, highlighting its potential as a therapeutic option for TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, often accompanied by a high risk of recurrence and drug resistance. Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, has demonstrated potent anticancer properties and is widely used as an adjuvant treatment for liver, breast, gastric, colon, and non-small cell lung cancers. However, its effects and molecular mechanisms in GIST remain unclear., Aim: This study aims to explore the inhibitory effects and underlying mechanisms of Huaier on GIST through network pharmacology and experimental validation., Materials and Methods: Initially, we utilized a publicly accessible database to identify the core targets and principal pathways associated with Huaier's therapeutic effects on gastrointestinal stromal tumors. To further evaluate its biological impact, cell viability, proliferation, migration, and invasion were assessed through CCK-8 and EdU assays, wound healing tests, and Transwell experiments. Apoptotic cell death was quantified using flow cytometry analysis. Additionally, the influence of Huaier extract on the expression levels of JAK2 and STAT3 proteins was examined via Western blotting. Finally, a subcutaneous xenograft mouse model was employed to investigate the anti-tumor efficacy of Huaier in vivo., Results: In this study, GAPDH, TNF, STAT3, ESR1, EGFR, IL6, CCND1, PTGS2, BCL2L1, and MAPK3 were identified as shared molecular targets, with the JAK/STAT signaling pathway recognized as the pivotal regulatory mechanism. Experimental findings demonstrated that Huaier exerted inhibitory effects on the proliferation, migration, and invasion of GIST-T1 and GIST-882 cells, exhibiting both dose- and time-dependent responses. Furthermore, Huaier was found to promote apoptosis in these cells. Western blot analysis revealed that treatment with Huaier extract significantly decreased the phosphorylation levels of JAK2 and STAT3, thereby suppressing the activation of the JAK2/STAT3 signaling cascade. In vivo experiments further substantiated these findings, showing that Huaier treatment markedly reduced tumor size and inhibited tumor progression., Conclusions: Our results suggest that Huaier may inhibit the growth of GIST cells by inhibiting the JAK2/STAT3 signaling pathway, reduce cell proliferation, induce apoptosis, reduce cell migration and invasion, and show anti-tumor effects in vivo and in vitro., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have no known competing financial interests or personal relationships., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Sphagneticola trilobata was traditionally used to alleviate wounds using topical plant preparations. The precise mechanism of the plant responsible for its wound healing effect are still unclear. Although the plant was reported to be cytotoxic, there is a lack of reported data regarding its cytotoxic impact on skin cancer., Aim of the Study: To in-depth investigate wound healing and cytotoxic effects of the plant extracts and its fractions by using different assays., Materials and Methods: In vitro scratch assay and in vivo full-thickness wound model were performed to evaluate the plant's wound healing activity. Enzyme-linked immunosorbent assay kits were employed to assess key skin parameters levels. The cytotoxicity was evaluated using in vitro Western Standard Time assay against skin carcinoma cells., Results: Sphagneticola trilobata improved the wound closure percentage in both in vitro scratch assay and in vivo model by modulating inflammation, as evidenced by a reduction in tumor necrosis factor and mitogen activated protein kinase levels, and enhancing proliferation via elevating collagen, smooth muscle actin, and forkhead protein. The total extract's efficacy surpassed the effectiveness of reference ointment. The non-polar fraction outperformed the polar one in accelerating wound closure and improving the tested skin parameters levels. Trilobolide-6-O-isobutyrate displayed the best docking scores for the selected target receptors. Moreover, the non-polar fraction demonstrated the most powerful cytotoxic effect against skin cancer cells. A specific compound mixture (kaurenoic acid/grandiflorenic acid, 1 and 2) within this fraction exhibited stronger cytotoxicity., Conclusions: Sphagneticola trilobata can be considered as a promising therapeutic agent in relieving wounds and combating skin cancer cell lines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Gastric cancer (GC) is a highly malignant tumor of the digestive tract, posing a significant menace to human health. Gancao Xiexin Decoction (GCXXD), being a traditional Chinese medicine (TCM), has a good effect on inhibiting the proliferation and metastasis of GC. However, its mechanisms still need further investigation., Aim of Study: To investigate the mechanism by which GCXXD inhibits GC metastasis through network pharmacology, and to verify through in vivo and in vitro experiments., Materials and Methods: The TCMSP and GEO databases, in combination with UPLC-MS/MS techniques, were employed to identify the hub genes, active ingredients, and critical pathways of GCXXD in the treatment of GC. Subsequently, molecular docking was conducted on both the hub genes and the core components. Finally, based on the results of the bioinformatics analysis, the role of GCXXD in inhibiting liver metastasis of GC was elucidated through in vivo and in vitro experiments, including scratch assays, Transwell assays, HE staining, immunohistochemistry, in vivo live imaging, qRT-PCR, and Western blotting., Results: Utilizing UPLC-MS/MS and network pharmacology, we identified 20 active ingredients and 5 hub targets in the treatment of GC by GCXXD. Through KEGG analyses, GCXXD treatment of GC could through the TGF-beta pathway. In vivo and in vitro experiments, GCXXD downregulated the mRNA and protein expression level of hub genes involved in the TGF-β1/SMAD pathway and the EMT process. Additionally, GCXXD significantly reduced the incidence of liver metastases in GC., Conclusion: GCXXD inhibited EMT via blocking the TGF-β1/SMAD pathway, which suppressed GC cell growth and liver metastasis. This study provides data to support the treatment of liver metastasis in GC with TCM and holds significant importance for the research and development of new anticancer drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy., Competing Interests: Competing interests statement:P. Zheng and Y.L. are co-founders and have equity interest in OncoC4. Other authors declare no competing interests. Patent application submitted on antibody variants.

Loading drug-maleimide (MAL) conjugates into liposomes preloaded with glutathione (GSH) can prepare the liposome encapsulating GSH-conjugated prodrugs, which serve as a feasible way to construct liposomal formulation. However, the effects ofthelinker on the development of this liposomal system remained unclear. Herein, docetaxel (DTX)-MAL conjugates linked by various linkers were used for such studies. It was found that the linker influenced the aqueous solubility of DTX-MALs, which further affected their loading efficiency in liposomes. The linker significantly influenced the DTX release from liposomal DTX-GSH (DTX-LIPs) by impacting the activation rate of DTX-GSH outside liposomes. Notably, DTX-LIPs containing the rapidly-activated DTX-GSH exhibited much more potent antitumor activity in the 4T1 breast cancer xenograft than other DTX-LIPs and commercial DTX injections. Analysis of the drug release mechanism revealed that DTX-GSH was first released from theliposome and consequently activated into DTX, and the prodrug activation was the rate-limiting step for DTX release. These results highlighted the crucial role of linkers in the drug loading, drug release, and antitumor activity of DTX-LIPs prepared by active click loading, which would effectively guide the rational design of liposomal drugs for improved antitumor efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The combination of chemotherapy and photothermal therapy not only improves the therapeutic effect but also limits the side effects of drugs. Herein, a multi-responsive dual-modality bone-targeted drug delivery vehicle for the treatment of osteosarcoma was designed by utilizing alendronate sodium as a bone-targeting ligand for the targeted delivery of doxorubicin (DOX) loaded polydopamine nanoparticles (PDA NPs) coated with γ-polyglutamic acid (APC@PDA/DOX NPs). The average size of spherical NPs was 140.0 nm with a zeta potential of -25.63 mV. The drug loading and encapsulation efficiency were 11.63 % and 96.44 %, respectively. The constructed NPs were responsive to acidic pH, redox conditions, and near-infrared light as the drug release rate of the system reached 70 %. Cell experiments showed that APC@PDA/DOX NPs significantly enhanced cytotoxicity in mouse K7M2 osteosarcoma cells due to PDA-induced hyperthermia and DOX-induced cytotoxicity. Compared with the free DOX solution, the area under the curve of APC@PDA/DOX NPs increased by 8.52 times, iterating the significantly prolonged circulation time of NPs in vivo that manifested in higher bioavailability. The biodistribution study showed that APC@PDA/DOX NPs enacted excellent bone targeting and tumor tissue localization. In general, APC@PDA/DOX NPs may offer a feasible and effective strategy for osteosarcoma-targeted therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Copper sulfide nanoparticles (CuS NPs) have garnered significant attention in photothermal therapy (PTT) owing to their facile synthesis, biodegradability, stability, and excellent photothermal conversion efficiency. Nonetheless, their potential toxic effects have restricted their application. This research focuses on the encapsulation of CuS NPs with the biocompatible polymer poly(lactic-co-glycolic acid) (PLGA) to enhance their biocompatibility, thereby improving the efficacy and safety of PTT in the treatment of triple-negative breast cancer (TNBC). Three distinct methods, namely aqueous phase loading method, oil phase loading method, and "in situ reduction" method were employed to synthesize PLGA-coated CuS (CuS@PLGA) NPs to optimize the encapsulation rate of CuS. Among these, the CuS@PLGA NPs fabricated via the "in situ reduction" method demonstrated the highest encapsulation efficiency for CuS, achieving a rate of (90.4 ± 3.3)%. The resulting CuS@PLGA NPs exhibited high stability, excellent photothermal effect, and good tumor-targeting ability. Moreover, CuS@PLGA NPs demonstrated enhanced anti-tumor efficacy and biocompatibility compared to CuS NPs in both in vitro and in vivo experiments. Consequently, this study offers an effective and safety strategy for PTT treatment of TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Chemotherapy hardly achieves satisfactory therapeutic efficacy owing to the widely occurred adverse effects and drug tolerance, and the extensively investigated delivery systems suffer from complicated synthesis, low drug loading and less efficient tumor accumulation. Herein, we developed rod-shape nanocrystals to address challenges in the circulation stability, tumor targeting and therapeutic efficacy of camptothecin (CPT), a mainstay of treatments for various cancers. CPT nanorods (CNR) were coated with polydopamine (PDA) to achieve combinational chemo- and photothermal therapies (PTT) and then wrapped with cell membrane (CM) from homotypic tumor cells to obtain CNR@PDA-CM. CNR@PDA-CM retained the membrane proteins presented on 4 T1 cell surface, holding the potential to decrease phagocytic uptake and selectively accumulate in tumor cells. The integration of rod shape and CM wrapping prolongs blood circulation, and CNR@PDA-CM achieves 73-fold longer terminal half-life and nearly 5-fold higher tumor accumulation than free CPT after intravenous injection. When reaching tumor sites, PDA-mediated photothermal effect accelerates CPT release and enhances drug permeability in tumors. The combination of PTT and CPT-based chemotherapy produce robust and synergistic therapeutic outcome in metastatic breast cancer, with almost compete inhibition of tumor growth and 100 % mouse survival at the end of experiment. Thus, this study demonstrates a concise design of CNRs with high drug loading, desirable homotypic targeting, synergistic antitumor efficacy to potentially provide new insight for effective treatment of metastatic cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Disulfiram (DSF), which has been traditionally used to treat alcoholism, has been shown to inhibit tumor growth, indicating its potential as an anticancer agent. However, its development and application are hindered by its poor water solubility, instability in physiological environments, and low bioavailability. In this study, phenylboronic acid-chitosan (PBA-CS) grafts were synthesized using the carbodiimide method. PBA-CS-modified DSF PLGA nanoparticles (DSF@PBA-CS-PLGA NPs) were constructed by coating the nanoparticle surfaces with PBA-CS to improve the stability of DSF in physiological environments and enhance its anti-tumor effects. The structures of PBA-CS and the DSF@PBA-CS-PLGA NPs were confirmed using FTIR UVs, DLS, ELS, TEM, 1 HNMR, DSC. Our in vitro degradation experiments showed that PBA-CS-PLGA NPs significantly improved the stability of DSF in physiological environments. Cell experiments showed that PBA-CS-PLGA NPs improved drug uptake and strongly inhibited HepG2 cell migration. A mouse tumor model was established using Dutch H22 cells. DSF@PBA-CS-PLGA NPs showed better tumor-targeting ability than DSF@PLGA NPs, with a tumor inhibition rate of more than 60%, and they induced apoptosis and inhibited neovascularization in mouse tumor tissues. Both the in vitro and in vivo experiments indicated that the DSF@PBA-CS-PLGA NPs overcame the limitations of DSF, improving the dissolution rate and stability of the drug, ultimately offering low toxicity, sustained release, and targeted delivery. These findings demonstrated the potential of DSF@PBA-CS-PLGA NPs for hepatic carcinoma therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The current research discusses polymer conjugation, formulation development, and evaluation of sorafenib-loaded polymeric nanomicelles of conjugated soluplus (solu-tin) and polymeric mixed nanomicelles of conjugated soluplus (solu-tin) with conjugated poloxamer 188 (polo-tin) for site-specific posterior segment delivery to the retina in managing retinoblastoma. Firstly, the soluplus and poloxamer 188 were conjugated with biotin by Fischer esterification reaction and evaluated by FTIR and 1 H NMR for confirmation of covalent bond formation involving the carboxyl group of biotin and hydroxyl group of polymers. Secondly, the sorafenib-loaded solu-tin nanomicelles and mixed nanomicelles of solu-tin with polo-tin were formulated by the thin film hydration method. Thereafter, these nanomicelles were evaluated and displayed suitable outcomes for particle size (78.53 nm and 73.17 nm), PDI (0.089 and 0.074), zeta potential (-3.65 mV and -4.17 mv), entrapment efficiency (99.23 % and 99.83 %), in vitro drug release (4 h and 8 h), solid-state analysis, osmolality (290 mOsm/kg and 293 mOsm/kg), pH (7.4 and 7.4), TEM (spherical) and residual solvent analysis (287.90 ppm and 363.49 ppm). The ex vivo transcleral permeation at 8 h was found to be 548.45 ng/cm 2 and 281.61 ng/cm 2 , respectively. Both the drug-loaded nanomicelles displayed a dose-dependent anticancer effect on Y-79 cells at all time points i.e. 6, 12, 18, and 24 h, and were non-toxic to normal retinal pigmented epithelial cell line (ARPE-19) when incubated for 24 h. Furthermore, the formulations were non-irritant (HET-CAM) and stable for 6 months. Hence, the developed technology is safe and efficacious for targeting the retina in managing retinoblastoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Surgical resection and postoperative adjuvant chemotherapy have enhanced the outlook for breast cancer patients. However, tumor relapse and serious side effects of chemotherapy continue to impact patients' quality of life. Designing injectable composite hydrogel made of biodegradable polymers providing sustained release of antiangiogenic and chemotherapeutic agents might play a vital role in elimination of cancer cells. In this regard, we developed dextran based composite hydrogel incorporating doxorubicin-loaded dual-sensitive pH-redox nanogels (DOX-DSNG) and combretastatin A4 (CA4) loaded liposomes which undergo rapid disassembly in cancer cells. CA4 prevents tubulin polymerization and thus inhibits angiogenesis by binding to vascular endothelial tubulin. The results showed that DOX-DSNGs were negatively charged and 144.8 ± 0.85 nm in size. Besides, the size of CA4 loaded liposomes were 102.35 ± 4.22 nm and were negatively charged. Encapsulation efficiency of DOX-DSNGs and CA4 loaded liposomes were 100 % and 89 %, respectively. After loading into the hydrogel structure, doxorubicin and CA4 were gradually released from the composite hydrogel for up to 21 days. DOX-DSNGs and CA4 loaded liposomes showed a dose-dependent cytotoxic effect against 4 T1 breast cancer cells. Thereafter, the anti-neoplastic effect and survival study of the composite hydrogel was evaluated in vivo in tumor-bearing mice. The composite hydrogel significantly reduced tumor volume (from 116 mm 3 to 38 mm 3 ) with negligible organ damage, while showed lower cardiotoxicity in 28 days. In conclusion, our results revealed that injectable composite dextran-based hydrogel incorporated with DOX-DSNG and CA4 loaded liposomes could be used as an efficient delivery platform for combination therapies in treatment of solid tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The limited selectivity and high systemic toxicity of traditional chemotherapy hinder its efficacy in treating diffuse large B-cell lymphoma (DLBCL). The combination of sonodynamic therapy (SDT) with chemotherapy has emerged as a novel strategy for cancer treatment, aiming to improve therapeutic outcomes and reduce systemic toxicity. However, challenges such as elevated drug clearance rates and non-selecitivity remain to be resolved. This study has developed a biocompatible nanomedicine delivery system, PA-HM@DOX/ICG, employing hollow mesoporous silica nanoparticles (HMSNs) as the nanocarrier. The nanomedicine incorporates the chemotherapeutic agent doxorubicin (DOX) along with the sonosensitizer indocyanine green (ICG) within its encapsulation, and undergoes additional surface modification using lipid-nucleic acid conjugates (DSPE-PEG-AS1411) to facilitate active targeted delivery. In vitro cellular experiments have validated that PA-HM@DOX/ICG can specifically recognize and be internalized by SU-DHL-4 lymphoma cells due to the overexpression of nucleolin on their surface. The synergistic effects of DOX-induced DNA damage and reactive oxygen species (ROS) generated by ultrasound-activated ICG induce apoptosis in these cells. Furthermore, PA-HM@DOX/ICG displays minimal toxicity towards LO2 normal hepatocytes, indicating a favorable biosafety profile. In vivo animal studies have shown that PA-HM@DOX/ICG effectively accumulates in tumor sites in mice through both the enhanced permeability and retention (EPR) effect and nucleolin-mediated targeting. Under ultrasound irradiation, PA-HM@DOX/ICG significantly inhibits tumor growth. This study introduces a nanoplatform that integrates chemotherapy with sonodynamic therapy, offering a novel approach for the efficient treatment of DLBCL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) remains a significant public health concern, emphasizing the need for innovative therapeutic strategies to improve patient outcomes. This study aimed to develop a highly efficient nanocarrier for targeted drug delivery, enhancing drug efficacy while minimizing concentrations and limiting adverse effects. We synthesized protein-based β-lactoglobulin (βlg) nanoparticles (NPs), loaded with 5-fluorouracil (5-FU) and sodium butyrate (NaB), and further functionalized with folic acid (FA) for specific targeting of folate receptor-positive CRC cells. The βlg-5-FU-NaB-FA nanoplatforms exhibited a well-defined size of 208 nm with a narrow size distribution (PDI ≈ 0.5). Zeta potential measurements showed a value of -11.4 mV, indicating stability and suitability for drug delivery. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed the nanocarrier's spherical morphology and efficient distribution. Drug release profiles demonstrated that the NPs released more drugs at neutral to alkaline pH levels, attributed to pectin's ionization properties. The efficacy of the prepared βlg-5-FU-NaB-FA nanoplatforms was investigated on HCT116 and Caco2 CRC cells, along with the normal cell line CRL-1831. The βlg-5-FU-NaB-FA nanoplatforms exhibited remarkable cytotoxicity against both HCT116 and Caco2 CRC cells compared to free drugs, highlighting the efficacy of targeted delivery in folate receptor-positive cells. These NPs induce cell apoptosis and cell cycle arrest more effectively than free drugs, demonstrating their potential for targeted cancer therapy. Furthermore, a decrease in the expression of crucial genes involved in the Wnt signaling pathway was observed, which offers a valuable understanding of their underlying mechanism. Collectively, our results suggest that the FA-targeted βlg nanocarriers represent a promising platform for the efficient and targeted delivery of 5-FU and NaB in folate receptor-positive CRC. This novel nanocarrier holds the potential to enhance therapeutic outcomes while minimizing side effects, providing a new avenue for the treatment of CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Bcl-2 protein plays an integral role in hijacking apoptosis and triggering chemoresistance in triple negative breast cancer (TNBC). The present study explored the therapeutic efficacy of Bcl-2 inhibitor i.e., venetoclax (VTX) loaded HP-β-CD NPs (VTX/HP-β-CD NPs) against TNBC. VTX/HP-β-CD NPs were prepared using nanoprecipitation method. The prepared nanoparticles had optimal size (∼217 ± 4.32 nm), narrow PDI (∼0.23 ± 0.01), higher drug loading (∼15.7 ± 1.94 %) and % entrapment efficiency (∼78.5 ± 1.09 %). Morphology assessment revealed a spherical shape. In-vitro release studies displayed sustained release for up to 72h. Moreover, VTX/HP-β-CD NPs exhibited higher cellular uptake, cytotoxicity, and apoptosis index than free drug. Furthermore, the IC 50 values for VTX/HP-β-CD NPs were significantly reduced in 4T1 (∼3.96-fold) and MDA-MB-231 (∼5.23-fold) cells. Additionally, VTX/HP-β-CD NPs showed remarkable potential to induce "mixed cell death" by reducing the glutathione (GSH) levels and increasing ROS in TNBC cells. The pharmacokinetic studies showed a marked increase in the AUC 0-∞ (∼2.12-fold), C max (∼1.05-fold), and t 1/2 (∼1.66-fold). Also, anti-cancer efficacy studies in 4T1-based model revealed improved therapeutic efficacy of VTX when delivered via HP-β-CD NPs. Safety evaluation revealed no signs of toxicity. Overall, the prepared nanocarrier holds significant promise in enhancing the payload and efficacy of VTX., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Norcantharidin (NCTD), an antitumor agent with an increased leukocyte function, has been used for the treatment of hepatocellular carcinoma (HCC) in clinical. However, the clinical application of NCTD is limited due to its inadequate hydrophilicity and lipophilicity, short half-life (t 1/2 ), as well as adverse effects such as vascular irritation, cardiotoxicity, and nephrotoxicity. Herein, a lactoferrin (Lf) and DSPE-mPEG 2000 functionalized liposomes loaded with norcantharidic acid (NCA), an active metabolite of NCTD, was constructed for the targeted therapy of HCC. In this study, blank PEGylated liposomes were prepared using the film hydration method, and the NCA was loaded by calcium acetate active loading method to increase the encapsulation efficiency (EE). Subsequently, lactoferrin was covalently coupled to DSPE-PEG 2000 -COOH activated by EDC and NHS. In addition, the in vivo pharmacokinetics and pharmacodynamics were investigated in Sprague-Dawley (SD) rats and H22 tumor-bearing BALB/c mice, respectively. As expected, the encapsulation efficiency measurement showed that the encapsulation efficiency of the NCA liposomes was 89.3±1.25 %, and the coupling efficiency of lactoferrin was more than 65.97 %. Additionally, the variations in both the dynamic size and encapsulation efficiency of norcantharidic acid liposomes in long-term storage stability and serum stability studies did not exceed 10 %. Furthermore, the pharmacokinetics and pharmacodynamics results showed that, the NCA-Lips-Lf were able to significantly improve antitumor activity by enhancing tumor-targeting accumulation and prolonging circulation time in the body compared to the sodium demethylcantharidate for injection (Na 2 DCA). Notably, the AUC 0-48 and the t 1/2 of NCA-Lips-Lf increased 4.28-time and 5.17-time in comparison to those of NCA-sol, respectively. The tumor inhibition rate of NCA-Lips-Lf (85.29 %) was significantly higher than that of sodium demethylcantharidate for injection (Na 2 DCA) (59.13 %), without obvious vascular irritation, cardiotoxicity and nephrotoxicity. In conclusion, NCA-Lips-Lf have the potential to eliminate hepatocellular carcinoma more effectively with fewer side effects than Na 2 DCA, which further advances the clinical application of norcantharidin-related drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Both photothermal therapy (PTT) and chemodynamic therapy (CDT) are designed to focus their antitumor effect on only the tumor site, thereby minimizing unwanted severe damage to healthy tissue outside the tumor. However, each monotherapy is limited in achieving complete tumor eradication, resulting in tumor recurrence. The combination of multiple therapies may help to overcome the limitations of single therapy, improve the chances of complete tumor eradication, and reduce the risk of recurrence. Here, we report a novel multifunctional carrier-free nanoparticle, namely Mn-TPP@ICG, prepared through the self-assembly of ICG and 5,10,15,20-Tetraphenyl-21H,23H-porphine manganese (III) chloride (Mn-TPP). The prepared Mn-TPP@ICG allowed dual-mode imaging in the form of magnetic resonance imaging (MRI) and near-infrared (NIR) fluorescence imaging, as well as combination therapy in the form of CDT and PTT. In vitro experiments revealed that Mn-TPP@ICG nanoparticles can enable CDT by converting intratumoral hydrogen peroxide (H 2 O 2 ) to highly cytotoxic hydroxyl radicals (·OH) and PTT through photothermal conversion, resulting in a strong synergistic antitumor effect. Furthermore, in vivo experiments revealed that CDT and PTT with Mn-TPP@ICG nanoparticles effected a synergistically enhanced therapeutic effect in 4T1 tumor-bearing mice, significantly inhibiting tumor growth compared with monomodal treatments with no treatment, only CDT, or only PTT. Lastly, imaging experiments unveiled the exceptional capability of Mn-TPP@ICG nanoparticles in enabling fluorescence imaging and high-resolution MRI upon their intravenous administration. Thus, a meaningful carrier-free nanoparticle strategy for the synergistic combination of CDT and PTT was provided in our study, broadening the applications of nanotheranostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

This study focuses on the preparation and characterization of platelet membrane biomimetic nanocarriers (P-PLGA NPs) and investigates their interactions with the transplacental barrier. Poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) were coated with platelet membrane (PLTM) to construct P-PLGA NPs. Additionally, fluorinated polyethylenimine (F-PEI) was grafted onto PLGA NPs to prepare F-PEI-PLGA NPs, which were compared with PLGA NPs. In vitro placental barrier cell models using human choriocarcinoma cells (BeWo b30) and in vivo pregnancy animal models using ICR mice were utilized to evaluate the transplacental barrier efficiency of the PLGA NPs with different surface modifications. The results demonstrated that all three types of nanoparticles could accumulate in the uterus and placenta. The transplacental barrier efficiency of F-PEI-PLGA NPs was found to be the highest at 4 h, while P-PLGA NPs exhibited the highest transplacental barrier efficiency at 12 and 24 h. Furthermore, there were no significant effects on the main organs, structure, and quantity of uterine spiral arteries, indicating the safety of the nanoparticles (NPs). P-PLGA NPs are expected to be a safe and effective nano-delivery system for perinatal drug delivery. This study provides insights into the transplacental barrier mechanism of NPs with different surface characteristics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Advanced cancer patients face a high risk of sepsis due to immune suppression and infection susceptibility. To tackle this challenge, we developed an innovative animal model that simulates the clinical scenario of late-stage cancer complicated by sepsis and designed a sialic acid (SA)-modified paclitaxel (PTX) liposome (PTX-SAL). This formulation specifically targets overactivated peripheral blood neutrophils (PBNs) by binding to L-selectin on their surface. It effectively eliminates hyperactive neutrophils and blocks their migration, thus reducing infiltration into tumor and inflammation sites. In sepsis and melanoma mouse models, PTX-SAL demonstrated superior therapeutic efficacy and a favorable safety profile. Notably, in the late-stage tumor model with sepsis, PTX-SAL significantly improved survival rates, with a 72-hour survival rate of 66.7%. In stark contrast, the PTX solution (PTX-S) group exhibited accelerated mortality, with all animals succumbing within 24 h, highlighting the detrimental effects of PTX-S's non-selective cytotoxicity on immune cells. These findings underscore the superior long-term safety and therapeutic advantage of nanomedicines like PTX-SAL over conventional drug formulations. In summary, SA-modified nanomedicines offer a dual benefit by targeting and eliminating inflammatory neutrophils, addressing both tumor progression and sepsis, and significantly reducing mortality in preclinical models. This innovative strategy fills a critical gap in the treatment of advanced cancer complicated by sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Breast cancer and its lung metastases pose significant threats to women's health worldwide, impacting their quality of life. Although several therapeutic strategies against breast cancer have been developed, they often cause serious side effects due to their high toxicity and low specificity. Therefore, novel therapeutic strategies that offer potent anti-tumor activity with minimal toxicity are urgently needed to combat the threat of breast cancer and lung metastases. Celastrol (Cela), a triterpenoid extracted from Tripterygium wilfordii, exerts anti-tumor effects by inhibiting tumor angiogenesis as well as tumor cell proliferation, invasion, and metastasis. However, its poor solubility and potential for severe organ toxicity hinder its clinical application. Therefore, in this study, we prepared Cela nanocrystals (Cela-NCs), which effectively increased the solubility of Cela and improved its bioavailability. Subsequently, Cela-NCs were encapsulated within the cell membrane (CCM) derived from breast cancer cells to generate CCM/Cela-NCs and leverage the homologous targeting ability of the CCM. Notably, CCM/Cela-NCs showed immune evasion and could homologously target tumor cells. Both in vitro and in vivo, CCM/Cela-NCs could effectively inhibit the growth and metastasis of breast cancer cells. They also exerted minimal hepatotoxicity in mice during treatment. In conclusion, this Cela-based biomimetic strategy that exploits the biological properties of tumor cells offers a new idea for the effective treatment of breast cancer and its lung metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck malignancies, characterized by a five-year survival rate that remains persistently below 50%, indicative of limited progress in therapeutic interventions. There is an urgent imperative to develop innovative therapeutic strategies, warranting the investigation of advanced treatment modalities. Nanocarriers offer a promising avenue by significantly enhancing drug properties and pharmacokinetics. Extracellular vesicles (EVs) are naturally occurring nanocarriers produced by cells and have become a focal point in drug delivery research. Quercetin, one of the most abundant dietary flavonoids, exhibits potent anticancer effects. However, its pharmaceutical application is hampered by poor water solubility, instability under physiological conditions, and low bioavailability. To overcome these obstacles, we propose using bio-derived EVs as carriers to co-encapsulate quercetin with the photosensitizer chlorin e6. This strategy leverages the intrinsic targeting capabilities of EVs for precise drug delivery to tumors, along with light-activated drug release, enabling rapid quercetin release under near-infrared light, effectively inhibiting cellular proliferation and inducing apoptosis in tumor cells. In vivo studies demonstrated that drug-loaded EVs exhibited robust tumor-targeting efficacy, resulting in effective and selective tumor ablation upon photoactivation in mice bearing subcutaneous MOC2 tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

A pivotal pathway of photodynamic therapy (PDT) is to prompt mitochondrial damage by reactive oxygen species (ROS) generation, thus leading to cancer cell apoptosis. However, mitochondrial autophagy is induced during such a PDT process, which is a protective mechanism for cancer cell homeostasis, resulting in undermined therapeutic efficacy. Herein, we report a series of meticulously designed donor (D)-π-acceptor (A) photosensitizers (PSs), characterized by the strategic modulation of thiophene π-bridges, which exhibit unparalleled mitochondrial targeting proficiency. Notably, TTBI within this series possesses remarkable ROS generation capability, which can directly trigger mitochondrial depolarization, thus effectively inducing apoptosis in cancer cells. Meanwhile, the damaged mitochondria activate the mitophagy process, which further boosts the ROS generation of the TTBI owing to the acidic environment in the lysosome, ultimately inducing lysosomal membrane permeability (LMP), thereby blocking the protective autophagy route and promoting extra apoptotic cell death. Accordingly, TTBI disrupts the integrity of mitochondrial and lysosome, leveraging a synergistic interplay between cellular compartments to achieve more potent apoptosis. This work provides new insights to overcome the limitation of PDT efficacy imposed by mitochondrial autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, company., (Copyright © 2025. Published by Elsevier B.V.)

Inflammation and oxidative stress are pivotal factors in the onset and progression of secondary injury following cerebral ischemia-reperfusion (I/R). Mogroside V (MV), a primary active compound of Siraitia grosvenorii, exhibits significant anti-inflammatory and antioxidant properties. However, its specific effects in cerebral ischemia remain unclear. In this study, we evaluated the neuroprotective effects of MV in a model of focal cerebral ischemia. Male C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) as an in vivo model of cerebral ischemia-reperfusion injury (CIRI), while U87 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate CIRI in vitro. MV administration was found to reduce mortality, infarct volume, cerebral edema, and alleviate neurological deficits in these I/R mice. Furthermore, MV mitigated cerebral I/R injury by decreasing oxidative stress markers, such as reactive oxygen species (ROS) and malondialdehyde (MDA), while enhancing superoxide dismutase (SOD) levels. Gene Set Enrichment Analysis (GSEA) of the KEGG pathway revealed that most differentially expressed genes (DEGs) were involved in the Toll-like receptor/NF-κB/TNF/apoptosis signaling pathway. These findings were confirmed by real-time PCR, western blotting, immunohistochemistry, and immunofluorescence co-localization which demonstrated that MV reduced astrocyte inflammatory responses by inhibiting cytokine secretion associated with the TLR4/TRADD pathway. Additionally, MV protected neurons from apoptosis, as supported by TUNEL, Nissl, and HE staining. In conclusion, MV attenuates astrocyte inflammation and exerts neuroprotective effects following cerebral I/R injury, likely through suppression of the TLR4/TRADD signaling pathway., (Copyright © 2025. Published by Elsevier B.V.)

Faced with the highly malignant challenge of lung cancer, traditional chemotherapeutic agents, although predominantly inducing apoptosis, are severely limited in their therapeutic effect by the overexpression of anti-apoptotic proteins in lung cancer. Recently discovered copper-induced non-apoptotic cell death, known as cuproptosis, represents a novel mechanism for regulating cell death. Whether Celastrol (Cel), a potential anti-tumor drug, can counter non-small cell lung cancer (NSCLC) through inducing cuproptosis remains to be thoroughly investigated. This study demonstrates that the copper chelator tetrathiomolybdate (TTM) is more effective in rescuing Cel-induced NSCLC cell death compared to other inhibitors. RNA sequencing revealed that Cel significantly upregulates the copper transporter protein SLC31A1. In addition, Cel also promotes intracellular copper accumulation, reduces GSH levels, and exhibits features of cuproptosis, including loss of iron-sulfur cluster proteins (FDX1, SDHB, POLD1), increased HSP70, and DLAT oligomerization. Experiments also found that Cel significantly increases reactive oxygen species (ROS) levels, reduces mitochondrial membrane potential, and lowers ATP levels. It was predicted through online databases that SRF may be the transcription factor for SLC31A1, and this was validated through overexpression experiments. In vivo data demonstrated that Cel significantly inhibits tumor growth without damaging the heart, liver, or kidneys of mice. This study first reveals that celastrol disrupts intracellular copper homeostasis through the SRF/SLC31A1 pathway, promoting cuproptosis in NSCLC cells, providing support for Cel as a potential safe and effective chemotherapeutic agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Cervical cancer (CESC) is a leading cause of death attributed to cancer worldwide. Advanced-stage cervical cancer presents unique challenges, such as few treatment modalities. Though DCBLD1 has been earlier connected to a variety of cancers, there has been no extensive investigation on DCBLD1 regarding cervical cancer. This study seeks to assess the expression and prognostic significance of DCBLD1 in multiple cancer types, heavily relying on cervical cancer, as well as its implications on immune modulation., Methods: The pan-cancer expression of box-like genes in DCBLD1 was investigated in 33 cancer types using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Survival analyses involving Overall Survival (OS) and Progression-Free Survival (PFS) were conducted to evaluate the relationship between DCBLD1 expression and the prognosis of these neoplasms. Furthermore, immune infiltration gene co-expression and tumor microenvironment (TME) analyses were performed. In vitro assays in cervical cancer cell lines were done to analyze the functional impact of silencing DCBLD1 on cell proliferation, migration, and invasion., Results: DCBLD1 was significantly overexpressed in 16 cancer types, including cervical cancer, and was associated with poor prognosis for several of these cancer types. In CESC, the expression of DCBLD1 was significantly associated with shorter OS and PFS. While immune infiltration analysis showed a significant association for DCBLD1 with several immune cells, including CD4+ memory T cells and macrophages, the functional assays demonstrated that silencing DCBLD1 in cervical cancer cells inhibited their cell proliferation, migration, and invasion, implicating it in tumor progression., Conclusions: DCBLD1 could serve as an amendable biomarker of poor prognosis in cervical cancer and other cancers whose high expression level correlates with immune infiltration, which may suggest its role in modulating the tumor microenvironment. This shows that targeting DCBLD1 could prove effective as a potential therapeutic modality in conjunction with other immune-based therapies for cervical cancer., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Tumor vasculature exhibit numerous abnormal features distinct from those of healthy vessels, potentially advancing tumor development by establishing an aberrant microenvironment. Therefore, vascular normalization has proven to be an effective tactic for substantially enhancing treatment efficacy across multiple tumors. However, the methods to attain vascular normalization may vary among tumor types. VE-PTP, expressed exclusively in vascular endothelial cells (ECs) and acting as a critical suppressor of vascular maturity and functionality, is upregulated in oral cancer due to hypoxia. In this study, we explored the effect and mechanism of AKB-9778, a competitive inhibitor of VE-PTP, in promoting vascular normalization of oral cancer. Initially, we showed that AKB-9778 can slow down tumor progression by fostering vascular normalization in a murine OSCC model. This was evidenced by improvements in vessel density, pericyte coverage, local hypoxia, and vascular permeability. RNA sequencing additionally indicated that the ECs of tumor vasculature exhibit abnormal alterations in adhesion molecules, and AKB-9778 treatment might facilitate vascular normalization by modulating lipid metabolism pathways, especially HSD17B7-regulated steroid biosynthesis. AKB-9778 treatment significantly up-regulated the HSD17B7 expression, thereby restoring the lipid content in tumor ECs. Moreover, this restoration of lipid metabolism mediated by HSD17B7 was associated with improved adhesion molecule expression and vascular normalization, facilitating immune cell infiltration and contributing to AKB-9778's anti-tumor effects. Finally, we verified the effects and safety of combined AKB-9778 treatment on improving the efficacy of anti-PD-1 immunotherapy. In summary, this study revealed the mechanism and potential application of AKB-9778-induced vascular normalization in patients with oral cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Corynoline (COR) is an isoquinoline alkaloid derived from the traditional Chinese medicine Corydalis bungeana Turcz, known for its analgesic, antibacterial, neuroprotective, and osteoporosis-alleviating properties. However, its potential molecular effects against osteosarcoma (OS) remain unclear, warranting further investigation. This study demonstrated that COR inhibits OS cell proliferation and promotes apoptosis in a dose-dependent manner. Additionally, COR induced G2/M phase cell cycle arrest. Using an integrative computational and experimental approach, we found the Src/JNK pathway was identified as a significant target. Western blot analysis revealed that OS cells treated with COR showedan increase in levels was evident of p-Src, p-JNK, and p-c-JUN. Moreover, the JNK inhibitor SP600125 counteracted COR's anti-proliferative effects and reversed mitochondrial apoptosis and cell cycle arrest. In vivo, COR significantly reduced tumor size in OS xenograft nude mice without causing toxicity. Following COR treatment, elevated levels of p-JNK and cyclin B1 were observed, while Ki-67 decreased and JNK levels remained unchanged. We finally elucidated the COR inhibits OS via Src/JNK pathway. Given its multifaceted roles in regulating cell behavior in the context of OS, the Src/JNK pathway is being explored for therapeutic interventions. Targeting this pathway could potentially improve treatment outcomes by modulating the balance between cell survival and death in OS. Thus, understanding the Src/JNK pathway is essential for unraveling the intricate mechanisms underlying OS progression and for developing effective therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Chimeric antigen receptor T (CAR-T) cell therapy targeting B cell mature antigen (BCMA) has shown remarkable clinical benefits in treating multiple myeloma (MM). Bortezomib, a proteasome inhibitor approved as a first-line agent for MM for two decades, has demonstrated potent antitumor activity. In this study, we found that bortezomib treatment stabilizes the expression of BCMA and conceived the hypothesis that BCMA CAR-T therapy combined with bortezomib would enhance the anti-MM efficacy. The in vitro experiments revealed that pretreatment of both MM tumor cell line MM1.S and tumor cell line NALM-6 forced expression of BCMA with low concentrations of bortezomib up-regulated BCMA expression. When encountered with BCMA CAR-T cells, the cytotoxicity to these bortezomib-treated tumor cells was increased, indicating that the up-regulated BCMA induced by bortezomib contributes to the enhanced activities of the CAR-T cells. Further, in the in vivo experiment, the combined treatment significantly enhanced the anti-MM ability and prolonged the survival rate. Moreover, safety analysis found that there is no tissue damage or loss of weight, suggesting the favorable tolerability of this combination strategy. Our study provided a surety and efficacious strategy for the BCMA-targeted CAR-T cancer immunotherapy enhancement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: To investigate the role of long non-coding RNAs (lncRNAs) in the metabolic reprogramming of gastric cancer through their regulation of mesenchymal stem cells (MSCs) and HERPUD1 protein targets, aiming to elucidate mechanisms that could lead to novel therapeutic strategies., Method: The RNA-seq was performed on BGC and hMSC-BGC cells to perform LncRNA screening. And we employed cell culture techniques using hMSC-BM and BGC823 cells, treated with various genetic interventions including siRNA and overexpression vectors. Techniques such as cell viability assays, quantitative PCR (qPCR), Western blotting, RNA pull-down and RNA-FISH were utilized to validate the interaction between lncRNA AC012181.2 and HERPUD1 protein. Flow cytometry were utilized to analyze the impacts of lncRNA AC012181.2 on gene and protein expression related to cancer metabolism. Additionally, a tumorigenic model in nude mice was used to observe the in vivo effects., Result: Modulation of AC012181.2 in MSCs significantly affected the proliferation, migration, and invasion capabilities of BGC823 gastric cancer cells. Knockdown of AC012181.2 resulted in reduced tumor growth in mouse models, along with changes in key gene and protein expression levels associated with cancer metabolism. Overexpression of AC012181.2 showed the opposite effect, enhancing tumor growth and altering cellular behaviors and molecular expressions in favor of cancer progression., Conclusion: The lncRNA AC012181.2 is crucial for gastric cancer metabolic reprogramming by regulating HERPUD1 Protein. Targeting it offers a promising avenue to impact the tumor microenvironment and develop novel gastric cancer therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Pyroptosis, a form of programmed cell death, has recently emerged as a compelling molecular mechanism associated with the efficacy of chemotherapeutic drugs in tumor treatment. OSW-1, derived from the bulbs of Ornithogalum saundersiae Baker, exhibits a diverse range of pharmacological effects. However, its specific antitumor effects on colorectal cancer (CRC) and the mechanisms underlying these effects remain elusive. In this study, we explored whether OSW-1 can induce pyroptosis in CRC cells, aiming to expand its potential clinical applications. Various functional experiments, including Cell Counting Kit-8 (CCK-8), plate colony formation, wound healing, and Transwell assays, were conducted to assess cell proliferation, migration, and invasion. The results of in vitro experiments revealed apparent inhibitory effects of OSW-1 on CRC cells, and we observed a pyroptosis-like morphology in treated cells by scanning electron microscopy (SEM). OSW-1 was found to induce pyroptosis through the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/cysteinyl aspartate specific proteinase-1 (Caspase-1) pathway, with the production of reactive oxygen species (ROS) mediating this pyroptotic pathway. The results from xenograft animal models further demonstrated that OSW-1 facilitated pyroptosis in CRC cells, significantly inhibiting tumor growth. In summary, our findings suggest that OSW-1 activates pyroptosis in CRC cells through the ROS/NLRP3/Caspase-1 pathway. These results provide valuable evidence regarding the role of pyroptosis in various tumor types, emphasizing the potential of OSW-1 as a therapeutic agent in tumor treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Exosomes derived from cancer cells significantly influence the tumor immune microenvironment and can limit the efficacy of immunotherapy. However, the impact of exosomes on B cell-dependent anti-tumor immunity remains poorly understood. Here, we demonstrate that exosomes secreted by MC38 (MC38-Exos), a murine colorectal cancer cell line, induce B cells to adopt immunosuppressive phenotypes. MC38-Exos inhibits B cell proliferation and survival. Additionally, MC38-Exos induce B cells to acquire characteristics of regulatory B cells, including the upregulation of IL-10 and TGF-β. Finally, B cells treated with MC38-Exos impair the functional efficacy of CD8 + T cells. Transcriptome analysis reveals that MC38-Exos markedly suppresses gene pathways associated with B cell receptor (BCR) signaling, as well as antigen processing and presentation in B cells, but up-regulates genes involving apoptosis pathway. Mechanistically, NF-κB pathway was enriched in KEGG analysis, and was validated by western blot. Finally, inhibition of MC38-Exo in vivo activates B-cell mediated anti-tumor immunity. Thus, MC38-Exo has a profound effect of transcriptome of B cells and attenuates B cell-dependent anti-tumor immunity, supporting the rationale for targeted exosome therapy in human colorectal cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

THSWD has the effect of reducing inflammation, improving microcirculation, and regulating immune status in patients with hepatocellular carcinoma. Regardless of its clear therapeutic effect, the underlying mechanism of action against hepatocellular carcinoma is not clear. To identify critical gut microbiota and its associated metabolites related to THSWD inhibition against hepatocellular carcinoma progression, we assessed the microbe-dependent anti-hepatocellular carcinoma effects of THSWD through 16 s rRNA gene sequencing, fecal microbial transplantation and antibiotic treatment. Metabolic analyses, transcriptomic analyses, and molecular experiments were performed to explore how THSWD modulates the gut microbiota against hepatocellular carcinoma progression. As confirmed by in vivo and in vitro assays, THSWD reduced tumour growth rate and promoted apoptosis in hepatocellular carcinoma cells in hepatocellular carcinoma model mice, and liver and kidney indexes were detected and confirmed the safety of THSWD. Transcriptomic analysis revealed that the targets of THSWD were significantly enriched in multiple lysosomal autophagy signalling pathways, suggesting that lysosomal autophagy is probably associated with THSWD's therapeutic effect. Based on the integrated data analysis, THSWD delays hepatocellular carcinoma progression by increasing the intestinal microbiota Duncaniella and augmenting the metabolite glabrol, and the joint analysis of metabolic and genomic data suggests that this metabolite is associated with lysosomal autophagy, and cellular experiments confirmed that the The differential metabolite glabrol induces apoptosis in hepatocellular carcinoma cells by triggering the lysosomal autophagy-mediated apoptosis signalling pathway. Supplementation with glabrol metabolites up regulates the LTF/AMPK/mTOR/Beclin1 axis and promotes hepatocellular carcinoma cells with lysosomal autophagy and induced apoptosis in hepatocellular carcinoma cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Long non-coding RNAs (lncRNAs) play important roles in progression of neuroblastoma (NB). LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to affect the development of multiple tumors. However, the effect of NEAT1 on NB remain unclear. In this study, the new mechanisms whereby how NEAT1 influences tumor progression in NB was investigated., Methods: RT-qPCR, western blot, bioinformatics, cell growth, Transwell, and flow cytometric analyses were performed to determine how NEAT1 synchronously regulates the miR-873-5p/MYCN proto-oncogene(MYCN) and miR-873-5p/polypeptide N-acetylgalactosaminyltransferase 1(GalNAcT-I) axes to accelerate the progression of NB. NB-bearing animal models were established to evaluate the function of NEAT1 in NB. The relationships between transcription factor coactivatorassociated arginine methyltransferase 1 (CARM1) and NEAT1, NEAT1 and miR-873-5p, miR-873-5p and GalNacT-I or MYCN, were verified using luciferase reporter gene assay, respectively., Results: Our study revealed elevated levels of NEAT1 expression in NB cells and tissues which was associated with an advanced pathological stage and poor prognostic outcomes. According to in vitro gain- and loss- of function experiments, NEAT1 enhances progression of NB. NEAT1 silencing was found to inhibit NB proliferation in vivo. Mechanistically, to achieve upstream regulation, epigenetic downregulation of NEAT1 was achieved via the inhibition of CARM1. NEAT1 was found to positively regulate MYCN and GalNAcT-I levels as a competitive sponge of miR-873-5p., Conclusion: Activity of the lncRNA NEAT1 can be triggered via CARM1, which synchronously promotes NB development via the miR-873-5p/MYCN and miR-873-5p/GalNAcT-I axes. These findings shed light on the novel molecular mechanisms underlying NB progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanoma is an aggressive form of malignancy that originates from melanin-producing cells known as melanocytes underlying the basal layer of the epidermis with a poor prognosis, low survival rates, and limited treatment options. Although several specific and effective systematic strategies for treating melanoma have been established, the underlying molecular mechanism of melanoma progression, mortality and the promising therapeutic options remain elusive. Shikonin (SK), a natural naphthoquinone derived from a medicinal herbaceous plant, has been shown to inhibit the proliferation of several cancer cells. However, its role in the context of melanoma is poorly understood. In the present study, the anti-melanoma activity of (2-methylbutyryl) Shikonin was assessed under in vitro and in vivo models. In vitro findings revealed that (2-methylbutyryl) Shikonin significantly reduced the viability and promoted apoptosis in the B16F10 melanoma cells. Additionally (2-methylbutyryl) Shikonin significantly suppressed migration and invasion of melanoma cells by regulating IKK/NFκB/EMT signalling axis thereby attenuating nuclear translocation and subsequent transcription of NF-κB downstream target genes. Furthermore, (2-methylbutyryl) Shikonin administration significantly reduced tumor size and weight in the xenograft melanoma mice model. Our data presents novel insights that justify additional preclinical and clinical validations of (2-methylbutyryl) Shikonin for melanoma therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

ROS (Reactive Oxygen Species) has a dual role in tumorigenesis. Some cancers have high ROS conditions, and others have low ROS. TNBC thrives on high ROS compared to other Breast Cancer subtypes. Several antioxidant enzymes catalyze the detoxification of reactive oxygen species and prevent free radicals from damaging DNA and accumulation of mutation. Curcumin, a polyphenol dietary supplement, acts as a potent antioxidant, is known to reduce inflammation, and has anticancer properties. Here, we aim to understand alterations in the transcriptome (miRNA and mRNA expression) induced by ST09 in breast cancer cell lines. We identified an antioxidant system that is upregulated in breast cancer cell lines. Among the antioxidant enzymes regulated by miRNA was GPX3. A novel miRNA-mRNA antioxidant axis, miR-197-5p/GPX3, was observed in the TNBC cell line. We further validated the regulation of GPX3 by miRNA using luciferase assay. GPX3 overexpression, knockdown, and activity assay indicated the anti-tumorigenic role of GPX3 in the TNBC cell line. Further, treatment of TNBC xenograft with ST09 showed tumor reduction in vivo. ST09 potentiates the effect of standard-of-care (SOC) drug Cisplatin in vivo. ST09 can be exploited as a single chemotherapeutic agent or in combination treatment modalities, reducing the dosage of potent drugs., (Copyright © 2025 Elsevier B.V. All rights reserved.)

This study investigated the expression pattern of Vesicular Amine Transporter 1 (VAT1) in gastric cancer (GC) and its impact on prognosis, alongside evaluating its potential as a biomarker for immunotherapy and chemotherapy. Analysis of transcriptomic data, supported by experimental validation, revealed that VAT1 is highly expressed in GC and is associated with poor prognosis. Kaplan-Meier and ROC analyses demonstrated VAT1's potential in GC diagnosis, while multivariate analysis confirmed its role as an independent risk factor. Gene set enrichment analysis indicated that VAT1 plays a role in regulating the MAPK signaling pathway and epithelial-mesenchymal transition (EMT) in GC. Immune infiltration analysis showed a positive correlation between VAT1 and immune cells, particularly macrophages, and a negative correlation with chemotherapy sensitivity. In vitro and in vivo experiments further confirmed VAT1's critical role in promoting GC cell proliferation and inhibiting apoptosis. Overall, VAT1 holds significant value not only in GC diagnosis and prognosis but also as a potential target for immunotherapy and overcoming drug resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: The immunosuppressive microenvironment negatively affects the efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. Fusion protein that combining extracellular domain of inhibitory checkpoint protein and the cytoplasmic domain of stimulatory molecule may improve the efficacy of CAR-T cells by reversing the suppressive signals., Methods: To generate optimal PD1-TLR10 fusion proteins, PD1 extracellular domain and TLR10 intracellular domain were connected by transmembrane domain from PD1, CD28, or TLR10, respectively. The fusion protein was co-expressed with second generation anti-CEA CAR in the same retroviral vector. The effector function and the efficacy of fusion protein armored CAR-T cells was evaluated in vitro and in vivo., Results: PD1-TLR10 armored CEA CAR-T cells showed stronger cytotoxicity and cytokine release against CEA-positive tumor cells. Specifically, CAR-T cells with fusion protein containing TLR10 transmembrane domain demonstrated better anti-tumor activity in xenograft mouse model., Conclusion: Our study demonstrated that CEA CAR-T armored with rational designed PD1-TLR10 fusion protein had improved efficacy in colon cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of TriArm Therapeutics and are among the inventors of patent application related to fusion proteins., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Renal cell carcinoma (RCC) is one of the most common urological malignancies worldwide, and advanced patients often face challenges with chemotherapy resistance and poor prognosis. Ferroptosis, a novel form of cell death, offers potential therapeutic prospects. In this study, we found that DJ-1 was elevated in kidney renal clear cell carcinoma (KIRC), and this abnormal expression pattern was closely associated with clinical pathological characteristics and worse prognosis. Our experiments both in vivo and in vitro revealed that DJ-1 enhanced the malignant characteristics of KIRC, leading to increased tumor growth. Additionally, DJ-1 inhibited ferroptosis through promoting homocysteine (Hcy) synthesis in the transsulfuration pathway in KIRC cells. Mechanistic studies revealed that O-GlcNAc transferase (OGT) mediated O-GlcNAcylation of DJ-1 was crucial for maintaining its homodimeric structure. Importantly, O-GlcNAcylation-deficient mutation of DJ-1 at T19 residue enhanced the interaction between S-adenosyl homocysteine hydrolase (SAHH) and the negative regulatory factor S-adenosyl homocysteine hydrolase-like-1 (AHCYL1), thereby inhibited the activities of SAHH and transsulfuration pathway. In summary, the oncogenic role of DJ-1 in KIRC was closely related to the reduction of ferroptosis, and the O-GlcNAcylation of DJ-1 exerted an antioxidant effect by activating the transsulfuration pathway. Therefore, DJ-1, specifically O-GlcNAcylation of DJ-1 could represent an important target for ferroptosis-based anti-tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies., Methods: A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la., Results: Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression., Conclusions: Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women. Effective treatment of cervical cancer is urgently needed. Tumor therapeutic vaccine is a research hotspot in tumor immunotherapy, and the tumor therapeutic vaccine based on attenuated live bacteria carrier has clinical application prospect because of its clear action site and high safety. The bacterial balanced lethal system uses nutritional screening instead of antibiotic screening to avoid the risk of the spread of antibiotic resistance. So it is generally recognized as a green carrier. In our early research, we have constructed two cervical cancer therapeutic vaccine candidates (LM-HPVCW-1 and LI-HPVCW-1) based on Listeria balanced lethal system via transforming the nutrient-deficient strains with nutrition gene complementary plasmid. The complementary plasmid contained the nutrition complementary gene, LM dal gene, and its Amp gene was replaced with asd gene to delete the antibiotic resistance. Besides, it carried the shuffled HPV-16 E6E7 fusion protein gene. In vitro experiments showed that the plasmid carried by the candidate strain could be stably passaged and the target protein could be successfully expressed. In this study, we proved that the two candidate strains were safe in vivo and induced cellular immune response. At the same time, by establishing a tumor-bearing mouse model, it was proved that the two vaccine strains combined immunization could effectively inhibit mouse tumors. The mechanism of tumor suppression may be related to breaking the immunosuppression of tumor microenvironment and inducing CD8 + T cell infiltration. The therapeutic vaccine for cervical cancer constructed in this study is expected to be further applied in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The Warburg effect serves as a crucial aspect of tumor metabolism, where tumor cells preferentially rely on glycolysis, despite its lower efficiency, over oxidative phosphorylation for energy production even under aerobic conditions. This reprogramming of glucose metabolism confers glioma cells with the capacity for survival and proliferation. Serving as a messenger for regulating transforming growth factor beta, intracellular pH, cell metabolism maintaining cellular bioenergetic homeostasis, SMAD family member 5 (SMAD5) plays a pivotal role in the malignant progression of glioma cells and aerobic glycolysis. Hence, we have identified the expression and function of SMAD5 in human glioma cells, aiming to clarify its role in glycolysis. qRT-PCR and Western blot, reveal that SMAD5 is significantly overexpressed in glioma cells. Knocking down SMAD5 can effectively suppress the proliferation and invasion of glioma cells, while promoting apoptosis, furthermore, downregulation of SMAD5 in vivo has been shown to significantly reduce the growth of xenograft tumors. Conversely, overexpressing SMAD5 enhances the proliferative and invasive capabilities of glioma cells, while suppressing apoptosis. Concurrently, alterations in the expression level of SMAD5 exert an impact on the expression of glucose transporter GLUT1 and crucial enzymes involved in glycolysis, namely HK2 and PKM2, ultimately influencing the glycolytic capability of glioma cells. Specifically, knockdown of SMAD5 suppresses glycolysis, whereas its overexpression enhances glycolytic activity. In conclusion, our data demonstrate that SMAD5 can influence the proliferation, invasion, and apoptosis of glioma cells by modulating glycolysis. This finding holds potential for the development of novel metabolic treatment strategies for glioma., Competing Interests: Declarations. Ethical Approval: The Ethics Committee of the Second Hospital of Hebei Medical University authorized this research (approval No.: 2024-AE337). Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study investigated the function of the Bloom syndrome RecQ helicase-like gene (BLM) in triple-negative breast cancer (TNBC)., Methods: The expression levels of BLM in breast cancer cells were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical analysis. Cell proliferation, apoptosis, migration, and invasion were evaluated using the CCK-8 assay, clonogenic assay, flow cytometry, wound healing assay, and Transwell assay, respectively. Autophagosomes were observed via transmission electron microscopy (TEM). The expression levels of LC3B, Beclin1, and p62 were also measured. A murine xenograft model was employed to examine the impact of BLM on TNBC tumor growth, with tumor weight and volume recorded. Hematoxylin and eosin (H&E) staining and immunohistochemistry were utilized to assess pathological changes and Ki67 expression in tumor tissues. Additionally, Western blotting analysis was conducted to determine the expression of p53, AMPK, phosphorylated AMPK (p-AMPK), mTOR, and phosphorylated mTOR (p-mTOR)., Results: The expression of BLM was elevated in BT549 cells compared to normal cells. Following BLM knockdown, BT549 cell proliferation was significantly reduced, while apoptosis was enhanced. The migration rate of cells in the siBLM group was markedly decreased, as were the invasion and metastasis rates. TEM results indicated an increased presence of autophagosomes in the siBLM group, with significantly elevated expression levels of LC3B and Beclin1, and a decreased expression level of p62. Tumor volume and weight in the shBLM group were significantly lower than those in the shCtrl group. The number of intratumoral cells decreased, with most exhibiting nucleolysis or disintegration. Ki67 expression in the tumor tissue was also notably reduced. Additionally, the expression levels of p-mTOR, p-AMPK, and P53 proteins in the shBLM group were decreased., Conclusion: The knockdown of BLM significantly inhibited cell proliferation, migration, and invasion, while promoting apoptosis. This effect may be mediated through the regulation of the p53-AMPK-mTOR pathway., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the National Guidelines for the Ethical Review of Laboratory Animal Welfare, and approved by the Animal Ethic Committee of Bengbu Medical College (Approval number 2021286). All human participants were reviewed and approved by the Ethics Committee of Bengbu Medical College (Approval number 2021215). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression., Competing Interests: Competing interests statement:The authors declare no competing interest.

Only a minority of patients benefit from current T-cell-focused adaptive immunotherapies, underscoring the need to engage innate immune cells, particularly macrophages, for multilayered tumor control. However, high-efficacy therapeutics capable of orchestrating multiple immune cells remain scarce. Herein, a dual stimuli-responsive nanoimmunomodulator (6EPP@si) that caters specifically to the tumor microenvironment (TME) is presented for the antitumor synergy of macrophages and T cells. Using the functional polymer-based carrier, we co-deliver the endoplasmic reticulum (ER)-localized photosensitizer 6E and small interfering RNA targeting CD47 (siCD47) into breast tumors. Within the acidic and high-glutathione TME, 6EPP@si undergoes self-lysosome escape and nanocleavage for precise, on-demand drug release. Consequently, siCD47 released into the cytoplasm enables potent CD47 silencing, while the ER-targeted photosensitizer 6E induces immunogenic cell death through reactive oxygen species-based ER stress, triggering the release of damage-associated molecular patterns, including calreticulin surface translocation. 6EPP@si enhances macrophage phagocytosis by modulating both antiphagocytic and prophagocytic signals and also promotes antigen presentation to activate T cells. In orthotopic breast tumor and spontaneous lung metastatic tumor models, this combined approach demonstrates robust antitumor effects and effective antimetastatic immunity, offering a meaningful strategy to simultaneously activate multiple immune cells for enhancing cancer immunotherapy.