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RNA degradation using ribonuclease targeting chimeras (RiboTACs) is a promising approach for cancer therapy. However, potential off-target degradation is a serious issue. Here, a RiboTAC is designed for tumor microenvironment triggered activation. The tumor microenvironment activated RiboTAC (TaRiboTAC) incorporates two pre-miR-21 binders, a near-infrared fluorophore IR780, an RGD targeting peptide and a phenylboronic acid caged ribonuclease recruiter. The caged ribonuclease recruiter is embedded in the molecule and exposed in acidic pH, the phenylboronic acid cage is removed by H 2 O 2 making the TaRiboTAC responsive to the acidic and high H 2 O 2 levels in the tumor microenvironment. It is shown the TaRiboTAC targets tumor tissue and degrades pre-miR-21. The degradation of pre-miR-21 by TaRiboTACs significantly increases the radiotherapeutic susceptibility of cancer cells achieving efficient suppression of human lung adenocarcinoma A549 tumors in living mice., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti-PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy., (©2024 American Association for Cancer Research.)

Harnessing the potential of hydrogel-based localized drug delivery systems holds immense promise for mitigating the systemic side effects associated with conventional cancer therapies. However, the development of such systems demands the fulfillment of multiple stringent criteria, including injectability, biocompatibility, and controlled release. Herein, we present an ultra-small peptide-based hydrogel for the sustained and targeted delivery of doxorubicin in a murine model of breast cancer. The hydrogel evades dissolution and remains stable in biological fluids, serving as a reliable drug reservoir. However, it specifically reacts to the high levels of glutathione (GSH) in the tumor microenvironment and releases drugs in a controlled manner over time for consistent therapeutic benefits. Remarkably, administration of a single dose of doxorubicin-loaded hydrogel elicited superior tumor regression (approximately 75% within 18 days) compared to conventional doxorubicin treatment alone. Furthermore, the persistent presence of the drug-loaded hydrogel near the tumor site for up to 18 days after administration highlights its enduring effectiveness. There is great clinical potential for this localized delivery strategy because of the minimal off-target effects on healthy tissues. Our findings underscore the efficacy of this smart peptide-hydrogel platform and pave the way for developing next-generation localized drug delivery systems with enhanced therapeutic outcomes in cancer treatment.

Resistance to immune checkpoint inhibitors (ICI) is common, even in tumors with T-cell infiltration. We thus investigated consequences of ICI-induced T-cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL1 receptor 1, enabling a synergistic response to IL1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T-cell activity can drive resistance in tumors responsive to IL1 and TNFα, with important therapeutic implications., (©2024 American Association for Cancer Research.)

Targeting the tumor microenvironment (TME) is an attractive strategy for developing new drugs with anticancer activity against triple-negative breast cancer (TNBC). Interleukins (ILs) are key players in the TME cytokine network promoting cancer progression. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signalling in several cancers, including BC, in which IL-20RA is highly expressed, correlating with poor prognosis and influencing tumoral characteristics such as proliferation, cell death, invasiveness, and TME activity. Therefore, elucidating the role of the IL-20RA signalling pathway could form the basis for developing new therapeutic strategies. This study aimed to identify selective bioactive ligands able to affect IL-20RA activity. Virtual screening of over 310,000 compounds from both the DrugBank and ZINC15 databases identified four potential hit compounds tested for their anticancer activity against TNBC in vitro cell lines. Notably, Ritonavir, a well-known Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitor, significantly inhibited cell proliferation (about 40% at 50 µM, p < 0.001). IL-20 preincubation counteracted Ritonavir's cytostatic effect while IL-20RA knockdown restored proliferation in Ritonavir-treated TNBC cells. In conclusion, these findings demonstrated that Ritonavir reduced TNBC cell proliferation through IL-20RA activity modulation, suggesting its potential repurposing as a therapeutic agent for TNBC management.

Gliomas are the most ordinary primary virulent brain tumours and commonly used clinical treatments include tumour resection, radiation therapy and chemotherapy. Although significant progress has been made in recent years in progression-free survival (PFS) and overall survival (OS) for patients with high-grade gliomas, the prognosis for patients remains poor. Chemoresistance refers to the phenomenon of decreased sensitivity of tumour cells to drugs, resulting in reduced or ineffective drug efficacy, and is an important cause of failure of tumour chemotherapy. Exosomes, a type of extracellular vesicle, are secreted by cancer cells and various stromal cells in the tumour microenvironment (TME) and transfer their inclusions to cancer cells, increasing chemoresistance. Furthermore, depletion of exosomes reverses certain detrimental effects on tumour metabolism and restores sensitivity to chemotherapeutic agents. Here, we summarised the correlation between exosomes and resistance to chemotherapeutic agents in glioma patients, the mechanisms of action of exosomes involved in resistance and their clinical value. We aimed to afford new thoughts for research, clinical diagnosis and intervention in the mechanisms of chemoresistance in glioma patients., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Glioblastoma (GBM), the most malignant brain tumor with high prevalence, remains highly resistant to the existing immunotherapies due to the significant immunosuppression within tumor microenvironment (TME), predominantly manipulated by M2-phenotypic tumor-associated macrophages (M2-TAMs). Here in this work, an M2-TAMs targeted nano-reprogrammers, MG5-S-IMDQ, is established by decorating the mannose molecule as the targeting moiety as well as the toll-like receptor (TLR) 7/8 agonist, imidazoquinoline (IMDQ) on the dendrimeric nanoscaffold. MG5-S-IMDQ demonstrated an excellent capacity of penetrating the blood-brain barrier (BBB) as well as selectively targeting M2-TAMs in the GBM microenvironment, leading to a phenotype transformation and function restoration of TAMs shown as heightened phagocytic activity toward tumor cells, enhanced cytotoxic effects, and improved tumor antigen cross-presentation capability. In the meantime, by induction of a function-oriented "gear effect", MG5-S-IMDQ treatment extended its impact systemically by enhancing the infiltration of type I conventional dendritic cells (cDC1s) into the tumor sites and bolstering adaptive immune responses. In sum, by precisely working on M2-TAMs as a unique target in tumor situ, the nano-reprogrammers successfully established a robust immune network that worked synergistically to combat tumors. This facile nanoplatform-based immunomodulatory strategy, serving as a powerful and convenient immune monotherapy or as a complementary treatment alongside other therapies like surgery, provided deep insights for advancing translational study in GBM., (© 2025 Wiley‐VCH GmbH.)

Lymph nodes are crucial immune foci as the primary target for cancer immunotherapy. However, the anti-tumor functions of tumor-draining lymph nodes (TDLNs) are critically suppressed by tumors. Here, a novel spatiotemporal nano-regulator is presented, designed to modulate the dendritic cells (DCs) in TDLNs, establishing a supportive niche for immune surveillance. The DC-mediated nano-regulator (DNR) is established by the self-assembly of an imidazoquinoline (IMDQ) prodrug, inhibitory immune checkpoint (ICP) siRNA, and mannan (a TLR4 agonist). This unique design leverages the spatiotemporal activation of TLR4 and TLR7/8, thereby optimizing DC maturation and cytokine production. This further promotes efficient T cell priming. Simultaneously, the ICP-targeting siRNA mitigates the tolerogenic effects induced by tumor-derived factors and TLR activation, preventing T cell exhaustion. In essence, DNR facilitates potent remodeling of TDLNs and the tumor microenvironment, activating the anti-tumor immunity cascade. When combined with vaccines, DNR greatly promotes tumor regression and the establishment of long-term immunological memory., (© 2024 Wiley‐VCH GmbH.)

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin-1 (IL-1) family is a major mediator for inflammatory responses and has functional role in both innate and adaptive immunity. We previously showed high activation of multiple IL-1 signaling molecules during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. In the current study, we identified RP-54745, a potential antirheumatic compound as IL-1 inhibitor, effectively repressed KSHV + PEL cell growth through inducing tumor cell apoptosis. By using an established PEL xenograft model, we found that RP-54745 treatment suppressed tumor expansion in mice. Also, RP-54745 treatment significantly reduced hyperinflammation in tumor microenvironment including myeloid cells and neutrophils infiltration, as well as blocking IL-1 signaling molecules expression in vivo. In addition, our transcriptome analysis revealed novel cellular genes and mechanisms for anticancer activities of RP-54745. Taken together, our data indicate targeting IL-1 production and signaling may represent promising therapeutic strategies against these virus-associated diseases., (© 2025 Wiley Periodicals LLC.)

Numerous nanoparticles have been utilized to deliver Fe 2+ for tumor ferroptosis therapy, which can be readily converted to Fe 3+ via Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe 3+ to Fe 2+ via Fenton reactions. Herein, a strategy of intratumor Fe 3+/2+ cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe 3+ , CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O 2 can be catalyzed into superoxide anion (O 2 • - ) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O 2 • - . The O 2 • - can react with Fe 3+ to generate Fe 2+ , and raise H 2 O 2 level via the superoxide dismutase. The generated Fe 2+ and H 2 O 2 can be fast converted into Fe 3+ and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe 3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large 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 © 2024 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved., Competing Interests: Declarations. Competing interests: Manmeet Singh Ahluwalia: Grants from Seagen and NIH. Consultation fees from Bayer, Kiyatec, Insightec, GSK, Xoft, Nuvation, SDP Oncology, Apollomics, Prelude, Janssen, Voyager Therapeutics, Viewray, CarisLifesciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, AnheartTherapeutics, Theraguix, MenariniRicerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir, EquilliumBio., QV Bioelectronics. Scientific Advisory Boardmemberships in Modifibiosciences., Bugworks. DSMC membership for VBI Vaccines. Stockshareholder in: Mimivax, Cytodyn, MedInnovateAdvisors LLC, TrisalusLifesciences. Graeme Woodworth: Grants from Focused Ultrasound Foundation, NIH, Maryland StemCenter Research Foundation. Clinical Trial Support from Insightec and Keep PunchingFoundation. Mustafa Khasraw: Grants or contracts from BMS, AbbVie, BioNTech, CNS Pharmaceuticals, Daiichi Sankyo, Inc., Immorna Therapeutics, Immvira Therapeutics, JAX lab for genomic research, and Personalis, Inc.; received consulting fees from AnHeart Therapeutics, George Clinical, Manarini Stemline, and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPG Bio. All other authors have no disclosures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study explores the mechanisms underlying chemotherapy resistance in ovarian cancer (OC) using doxorubicin (DOX) and topotecan (TOP)-resistant cell lines derived from the drug-sensitive A2780 ovarian cancer cell line. Both two-dimensional (2D) monolayer cell cultures and three-dimensional (3D) spheroid models were employed to examine the differential drug responses in these environments. The results revealed that 3D spheroids demonstrated significantly higher resistance to DOX and TOP than 2D cultures, suggesting a closer mimicry of in vivo tumour conditions. Molecular analyses identified overexpression of essential drug resistance-related genes, including MDR1 and BCRP, and extracellular matrix (ECM) components, such as MYOT and SPP1, which were more pronounced in resistant cell lines. MDR1 and BCRP overexpression contribute to chemotherapy resistance in OC by expelling drugs like DOX and TOP. Targeting these transporters with inhibitors or gene silencing could improve drug efficacy, making them key therapeutic targets to enhance treatment outcomes for drug-resistant OC. The study further showed that EMT-associated markers, including VIM, SNAIL1, and SNAIL2, were upregulated in the 3D spheroids, reflecting a more mesenchymal phenotype. These findings suggest that factors beyond gene expression, such as spheroid architecture, cell-cell interactions, and drug penetration, contribute to the enhanced resistance observed in 3D cultures. These results highlight the importance of 3D cell culture models for a more accurate representation of tumour drug resistance mechanisms in ovarian cancer, providing valuable insights for therapeutic development., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The tumor microenvironment constitutes a complex system shaped by the intricate interactions among tumor cells, immune cells, and cytokines. Within this environment, the interplay between immune cells and cytokines is crucial in influencing tumor growth and progression. Despite advancements in clinical tumor immunotherapy, there remains a gap in comprehensive simulations of tumor immune responses, particularly regarding cytokine-driven processes. This study aims to address this gap by investigating the regulatory interactions among tumor cells, immune cells, and cytokines to simulate the complexities of tumor immunotherapy. We develop a comprehensive modeling and computational framework incorporating PD-1 inhibitors and interleukin-10 (IL-10) antibodies. Through detailed mathematical analysis, we elucidate the impact of changes in the immune microenvironment on tumor cells number. Our findings highlight the significant therapeutic effect of anti-PD-1 and IL-10 inhibitors, with increased drug dosage correlating with a reduction in tumor burden. Furthermore, combination therapy demonstrates a marked extension of survival with reduced dosages compared to monotherapy. Based on model simulations, we proposed prognostic predictions by assessing the microenvironmental status before treatment. The findings indicate a promising method for enhancing treatment effectiveness and offering potential advantages to patients receiving tumor immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Metastasis is one of the most important factors contributing to poor prognosis in hepatocellular carcinoma. Radiation therapy (RT), along with its induced abscopal effect, is a promising treatment for metastatic patients. However, the incidence of abscopal effect in clinical practice is rare, even when RT is combined with immune checkpoint inhibitors (ICIs). In this study, we aim to investigate the role of antiangiogenic treatment on the abscopal effect induced by RT + ICIs., Methods and Materials: Bilateral subcutaneous and orthotopic Hepa1-6 and Hep53.4 models were established and treated with different combination treatments. We evaluated changes in the immune microenvironment and vascular normalization by flow cytometry, T cell receptor sequencing, chemotactic gene array, enzyme linked immunosorbent assays, and immunofluorescence., Results: Our studies showed that antiangiogenic treatment with RT + ICIs increased the antitumor response of the unirradiated lesions. Mechanistically, the blockade of vascular endothelial receptor 2 (anti-VEGFR2) increased the activation and maturation of dendritic cells and promoted the production of CD8 + T cells in irradiated tumors. These CD8 + T cells were attracted by anti-VEGFR2-induced CCL5 secretion from M1 macrophages in unirradiated tumors. Besides that, anti-VEGFR2 enhanced the function of CD8 + T cells by reducing myeloid-derived suppressor cells and regulatory T cells., Conclusions: This study demonstrated that the combination of antiangiogenic treatment with RT and ICIs enhanced the abscopal effects. The application of triple therapy and its induced abscopal effect may offer a novel therapeutic approach for hepatocellular carcinoma, particularly for cases with multiple metastatic lesions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Transarterial chemoembolization (TACE) continues to stand as a primary option for treating unresectable hepatocellular carcinoma (HCC). However, the increased tumor hypoxia and acidification will lead to the immunosuppressive tumor microenvironment (TME) featuring exhausted T cells, limiting the effectiveness of subsequent therapies following TACE. Herein, a stable water-in-oil lipiodol Pickering emulsion by employing calcium phosphate nanoparticles (CaP NPs) as stabilizers is developed and used to encapsulate L-arginine (L-Arg), which is known for its ability to modulate T-cell metabolism. The obtained L-Arg-loaded CaP-stabilized lipiodol Pickering emulsion (L-Arg@CaPL) with great emulsion stability can not only neutralize the tumor acidity via reaction of CaP NPs with protons but also enable the release of L-Arg, thereby synergistically promoting the reinvigoration of exhausted CD8 + T cells and effectively reversing tumor immunosuppression. As a result, TACE therapy with L-Arg@CaPL shows greatly improved therapeutic responses as demonstrated in an orthotopic liver tumor model in rats. This study highlights an effective yet simple nanoparticle-stabilized Pickering emulsion strategy to promote TACE therapy via modulation of the immunosuppressive TME, presenting great potential for clinical translation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity., 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 (Z.F.L., X.L.Y. and C.X.) have submitted patent applications associated with this research. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine., 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.)

Extracellular acidosis stemming from altered tumor metabolism promotes cancer progression by enabling tumor cell adaptation to the hostile microenvironment. In osteosarcoma, we have previously shown that acidosis increases tumor cell survival alongside substantial lipid droplet accumulation. In this study, we explored the role of lipid droplet formation in mitigating cellular stress induced by extracellular acidosis in osteosarcoma cells, thereby enhancing tumor survival during progression. Specifically, we examined how lipid droplets shield against reactive oxygen species induced by extracellular acidosis. We demonstrated that lipid droplet biogenesis is critical for acid-exposed tumor cell survival, as it starts shortly after acid exposure (24 h) and inversely correlates with ROS levels (DCFH-DA assay), lipid peroxidation (Bodipy assay), and the antioxidant response, as also revealed by NRF2 transcript. Additionally, extracellular metabolites, such as lactate, and interaction with mesenchymal stromal cells within the tumor microenvironment intensify lipid droplet build-up in osteosarcoma cells. Critically, upon targeting two key proteins implicated in LD formation - PLIN2 and DGAT1 - cell viability significantly declined while ROS production escalated. In summary, our findings underscore the vital reliance of acid-exposed tumor cells on lipid droplet formation to scavenge oxidative stress. We conclude that the rewiring of lipid metabolism driven by microenvironmental cues is of paramount importance for the survival of metabolically altered osteosarcoma cells in acidic condition. Overall, we suggest that targeting key members of lipid droplet biogenesis may eradicate more aggressive and resistant tumor cells, uncovering potential new treatment strategies for osteosarcoma., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicola Baldini reports financial support was provided by Italian Association for Cancer Research. Nicola Baldini reports financial support was provided by National Recovery and Resilience Plan, PNRRM4C2. If there are other authors, they 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The utilization or improvement of tumor microenvironment (TME) has become a breakthrough in emerging oncology therapies. To address the limited therapeutic efficacy of single modality, a multi-functional integrated nanoplatform based on a TME-responsive PtAu/MnO 2 cascade nanoreactor with multi-enzymatic activities was developed for multimodal synergistic tumor therapy. Benefiting from the slightly acidic environment and high-level glutathione (GSH) in TME, PtAu/MnO 2 cascade nanoreactor consumed GSH, followed by the reductive generation of manganese ion (Mn 2+ ) and the release of PtAu nanoparticles (NPs). Then, the multimodal synergistic tumor therapy was activated as follows. First, GSH depletion inhibited the activity of glutathione peroxidase 4 and led to the accumulation of lipid peroxidation, thereby inducing tumor cell ferroptosis. Second, PtAu NPs exhibited catalase-like, glucose oxidase-like and nicotinamide adenine dinucleotide (NADH) oxidase-like activities, which generated oxygen for the cascade reaction to alleviate hypoxia and further depleted glucose, NADH and adenosine triphosphate, leading to the inhibition of tumor cell proliferation via starvation therapy. Third, the production of reactive oxygen species by the oxidase- and peroxidase-like activities of PtAu NPs and the Fenton-like reaction of Mn 2+ simultaneously induced tumor cell apoptosis via chemodynamic therapy. Briefly, the in vitro and in vivo results confirmed that the multi-functional integrated nanoplatform based on a PtAu/MnO 2 cascade nanoreactor with five nanozyme activities demonstrated outstanding biocompatibility and greater inhibition of tumor growth via synergistic ferroptosis/starvation therapy/apoptosis., 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 Inc. All rights reserved.)

In recent years, postoperative tumor therapy with a suitable approach has been an important issue. Remodeling the tumor microenvironment and accelerating tissue repair can accelerate patients' surgical site recovery, reduce patient pain as well as prevent postoperative tumor recurrence. The shape non-adaptability, cytotoxicity, and non-degradability of some hydrogels still hinder the application of hydrogel-based drug delivery systems in postoperative recovery. Natural polysaccharides (e.g., chitosan, sodium alginate, and hyaluronic acid) are multifunctional compounds with biomimetic advantages to meet the growing demand for nontoxic, targeted therapeutic, and restorative preventive therapies. In this paper, we comprehensively and systematically investigated the synthesis methods, properties, and applications of natural polysaccharide hydrogel (NPH) delivery systems, as well as the mechanisms of remodeling the tumor microenvironment. We aim to provide insights into the design of NPH delivery systems. On this basis, future research directions for NPH delivery systems and their role in remodeling the tumor microenvironment and accelerating postoperative tumor therapy are proposed, and strategies for remodeling the tumor microenvironment using hydrogel delivery systems are discussed, as well as the latest research methods., 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.)

Background: The influence of testosterone on the prostate's immune microenvironment remains unclear. This study aims to elucidate the dynamics of immune cells in the prostate following androgen deprivation therapy (ADT)., Methods: We retrospectively compared prostate needle biopsy and radical prostatectomy specimens from 33 patients who underwent both procedures, along with neoadjuvant ADT at a single institution. Immune cell infiltration in the cancer and stroma areas was assessed using multiplex fluorescence immunohistochemistry., Results: Post-ADT, all immune cells, including CD4 + T cells, CD8 + T cells, Foxp3 + regulatory T cells, CD204 + macrophages, and CD20 + B cells, significantly increased in the prostatectomy specimen. However, few immune cells were detected in the biopsy of the same patients (p < 0.001). The number of CD20 + B cells in the cancer area was significantly lower post-ADT in high-risk cases according to the NCCN classification (p = 0.020). This difference was significantly associated with the Gleason Grade Group, rather than PSA levels or T classification (p < 0.001). However, no significant difference was observed in the recurrence rate between Grade Groups 1, 2, 3 and 4, 5 (p = 0.991). There was no significant difference in immune cells other than CD20 + B cells when divided into NCCN classifications., Conclusions: The marked increase in immune cells following ADT suggests an intensified immune response against prostate cancer., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Cellular metabolism is inextricably linked to transmembrane levels of proton (H + ), sodium (Na + ), and potassium (K + ) ions. Although reduced sodium-potassium pump (Na + -K + ATPase) activity in tumors directly disturbs transmembrane Na + and K + levels, this dysfunction is a result of upregulated aerobic glycolysis generating excessive cytosolic H + (and lactate) which are extruded to acidify the interstitial space. These oncogene-directed metabolic changes, affecting intracellular Na + and H + , can be further exacerbated by upregulation of ion exchangers/transporters. As Na + /H + imbalances impact tumor invasion, chromosomal rearrangements, proliferation rate, angiogenesis, and immune function, measuring interstitial H + (H + o ) or pH (pH o ) and interstitial Na + (Na + o ) could provide unique insights into cancer hallmarks. We obtained proton ( 1 H) and sodium ( 23 Na) magnetic resonance spectroscopic imaging (MRSI) data to map pH o and Na + o in a human-derived glioblastoma model (U87) in vivo with sorafenib (protein kinase inhibitor) treatment and a placebo. In U87 tumors, sorafenib slowed tumor growth compared to placebo and restored transmembrane H + and Na + levels. Placebo tumors maintained an interstitial space that was less salty and more acidic, similar to naive U87 tumors, implying a proliferative state. However, sorafenib-treated tumors had interstitial space that became more salty and less acidic, comparable to normal tissue. Importantly, these interstitial ionic changes occurred prior to tumor growth changes. These results imply that glioblastoma therapies, which may perturb transmembrane ions by different mechanisms (e.g., ion pumping, exchange, and/or transport), can be tracked by merging 1 H with 23 Na MRSI to measure treatment effectiveness., (© 2025 John Wiley & Sons Ltd.)

The cellular components of the tumor microenvironment (TME) comprise cancer cells and nonmalignant cells including stromal and immune cells. Exosomes are extracellular vesicles secreted by various types of cells that play a crucial role in intercellular communications within TME. The main goal of this study was to elucidate how exosomes of macrophage cells treated with doxorubicin (DOX) and DOX-loaded cyclodextrin-based nanosponges (DOX-CDNSs), affect melanoma cancer cell proliferation. For this aim, the exosomes of the murine macrophage cell line (RAW 264.7) were isolated and characterized after treating the cells with DOX and DOX-CDNSs. The results demonstrated that DOX-CDNSs at a treatment concentration of 1 µg/mL, were nontoxic for macrophages and remarkably toxic against cancer cells. However, DOX was nontoxic for both cell types at the same treatment concentration. DOX and DOX-CDNSs remarkably declined the viability of both cell types at higher concentrations (25 and 50 µg/mL). Intriguingly, the exosomes of DOX-CD-NSs treated macrophages promoted the viability of cancer cells at the treatment concentrations of 1, 20, and 40 µg/mL. While the exosomes of DOX-treated macrophages increased cell viability of cancer cells only at the lowest concentration. In conclusion, this study suggests that utilization of CD-NSs may augment the toxicity of DOX against cancer cells, while it could direct macrophages toward secreting exosomes that favor the growth of cancer cells.

Lithium exposure reduces melanoma incidence and mortality, yet its therapeutic mechanisms are unclear. This study explores the effects of lithium on ferroptosis sensitivity and anti-tumor T cell response in melanoma. We found that lithium significantly enhanced RSL3-induced ferroptosis in vitro, evidenced by increased mitochondrial peroxide, lipid peroxidation, and mitochondrial abnormalities. Lithium also inhibited B16-F10 melanoma cell proliferation and migration in a dose-dependent manner. Cell cycle analysis showed lithium and RSL3 induced distinct perturbations, including G2/M and G0/G1 phase arrests. Mechanistically, lithium influenced intracellular ferrous ion levels by downregulating ferritin heavy chain (Fth1), crucial for iron homeostasis. The combination of lithium and RSL3 significantly suppressed tumor growth in mice, correlating with reduced Fth1 expression and increased iron deposition in the spleen and liver, highlighting a novel interaction between lithium and iron metabolism. Additionally, this combination enhanced CD8 + T cell infiltration and IFN-γ expression in the tumor microenvironment, especially among cytotoxic effector CD8 + T cells. These findings reveal the pro-ferroptotic and immune regulation roles of lithium, broaden our understanding of its biological roles, and propose new strategies for ferroptosis-targeted therapies in melanoma., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mutant EGFR is a common driver of non-small cell lung cancer (NSCLC). Although mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of patients with EGFR-mutant NSCLC benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR-mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment by promoting the expression of PD-L2 through reduced ubiquitination of c-MYC, and mutant EGFR cooperating to upregulate c-MYC and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced antitumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the tumor immune microenvironment of EGFR/CDKN2A co-mutant tumors and enhanced the antitumor efficacy of EGFR tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype. Significance: Upregulation of c-MYC driven by co-mutation of CDKN2A and EGFR increases PD-L2 to abrogate CD8+ T-cell activity in lung cancer, which confers sensitivity to PD-L2 blockade in combination with tyrosine kinase inhibitors., (©2024 American Association for Cancer Research.)

Nanozymes can improve reactive oxygen species (ROS)-based cancer therapies by targeting cancer cells' antioxidant defense mechanisms, particularly glutathione (GSH) depletion, to overcome ROS-resistant cancer cells. Nanozymes, innovative enzyme-mimetic nanomaterials, can generate ROS, alter the tumor microenvironment (TME), and synergize with photodynamic therapy (PDT), chemodynamic therapy (CDT), radiotherapy, and immunotherapy. This review shows how nanozymes catalyze ROS generation, selectively deplete GSH, and target cancer elimination, offering clear advantages over standard therapies. Nanozymes selectively target cancer cells' antioxidant defenses to improve PDT, CDT, and radiation therapies. To maximize nanozyme-based cancer treatment efficacy, biodistribution, biocompatibility, and tumor heterogeneity must be assessed. To improve cancer treatment, multifunctional, stimuli-responsive nanozymes and synergistic combination drugs should be developed.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zhuo Yu reports financial support was provided by National Natural Science Foundation of China. Zhuo Yu reports financial support was provided by Shanghai Municipal Education Commission. Jianfeng Guo reports financial support was provided by Science and Technology Department of Jilin Province. If there are other authors, they 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.)

The development of primary liver cancer (hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [ICC]) is linked to its physical microenvironment, particularly extracellular matrix (ECM) stiffness. Potential anticancer strategies targeting ECM stiffness include prevention/reversal of the stiffening process and disruption of the response of cancer cells to mechanical signals from ECM. However, each strategy has limitations. Therefore, the authors propose integrating them to maximize their strengths. Compared with HCC, ICC has a stiffer ECM and a worse prognosis. Therefore, ICC is selected to investigate mechanisms underlying the influence of ECM stiffness on cancer progression and application of the integrated anticancer strategy targeting ECM stiffness. In summary, immunofluorescence results for 181 primary liver cancer tissue chips (ICC, n = 91; HCC, n = 90) and analysis of TCGA mRNA-sequencing demonstrate that ECM stiffness can affect phenotypes of primary liver cancers. The YAP1/ABHD11-AS1/STAU2/ZYX/p-YAP1 pathway is a useful entry point for exploration of specific mechanisms of mechanical signal conduction from the ECM in ICC cells and their impact on cancer progression. Moreover, a synergistic anticancer strategy targeting ECM stiffness (ICCM@NPs + siABHD11-AS1@BAPN) is constructed by integrating ECM softening and blocking intracellular mechanical signal transduction in ICC and can provide insights for the treatment of cancers characterized by stiff ECM., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Post-surgical recurrence and extensive bone defects pose significant challenges during osteosarcoma treatment. These issues can be addressed using a novel strategy that promotes bone repair after removing residual tumors. Therefore, a 3D-printed porous polylactic acid (PLA) scaffold (PH-GBS@CCP) filled with hydrogel and surface-modified with nano-hydroxyapatite (nHA) is designed. The hydrogel, composed of gelatin modified with methacrylic anhydride (GelMA), sodium alginate (SA), and borax, contains Cu-Cys-PEG nanoparticles (CCP) modified with cRGD fk -PEG 2K -DSPE. It is injected into the PLA scaffold and crosslinked under UV. This hydrogel acts as a buffer medium between scaffold and bone, reducing cell abrasion, and as a carrier for the responsive release of tumor-targeting CCP. The scaffold provides the support and microenvironment required for bone repair. In early treatment, the acidic tumor microenvironment promotes hydrogel disintegration and CCP release, depleting glutathione and converting Cu 2+ to Cu + for the Fenton-like reaction. This generates reactive oxygen species, strengthening the proptosis effect, and killing the tumor. In later treatment, after tumor elimination, normalized pH and slow CCP release, along with scaffold nHA, promote osteogenic differentiation, providing a sustained osteogenic effect. Overall, the multifunctional composite scaffold achieved the sequential management of post-surgical osteosarcoma through early tumor-killing and later osteogenic effects., (© 2024 Wiley‐VCH GmbH.)

The tumor microenvironment (TME) exhibits characteristics such as hypoxia, weak acidity, and enrichment of glutathione and hydrogen peroxide (H 2 O 2 ), which greatly limits the effectiveness of tumor magnetic resonance imaging (MRI) and photodynamic therapy (PDT). Carbon dots (CDs) nanozymes are excellent candidate materials with both diagnostic and therapeutic potential. However, CDs nanozymes with both ultra-high relaxation rate and good therapeutic effect are still to be developed. Herein, novel carbon dots (MPC-CDs) were synthesized from polyethyleneimine (PEI), the photosensitizer hexahydroporphyrin (Ce6) and manganese. The Ce6 enabled the MPC-CDs to exhibit excellent PDT therapeutic ability, with a singlet oxygen yield as high as 1.52. The doping of the metal manganese gave the complexes CAT-like activity, and the singlet oxygen rate was further increased in the presence of H 2 O 2 , up to 1.97. In addition, manganese endowed the CDs with better MRI capabilities, and the r 1 and r 2 relaxation rates were significantly improved by 7.8-fold and 4.6-fold under acidic and H 2 O 2 conditions. The in vitro and in vivo results showed that MPC-CDs could achieve TME-responsive MR imaging and synergistic anti-tumor effects, providing an effective strategy to further enhance the effectiveness of tumor diagnosis and 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 © 2024 Elsevier B.V. All rights reserved.)

Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H 2 O 2 to oxygen (O 2 ) but also augmented intracellular ROS levels through the production of hydroxyl radicals (•OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model., Research Design and Methods: CD69 expression in GBM patient tissues was analyzed using the TCGA database. Therapeutic efficacy of anti-CD69 was tested in a murine GBM model with different regimens. Immune cell populations in the tumor microenvironment (TME) were assessed by flow cytometry., Results: Increased CD69 expression was observed in GBM patients compared to normal brain tissue and was associated with worse prognosis. Anti-CD69 treatment reduced percentages of CD69 + immune cells but did not improve survival in GBM-bearing mice. Increased PD-1 expression on NK cells was observed following anti-CD69 treatment. Anti-CD69 treatment was not improved by the addition of anti-PD-1 in vivo., Conclusions: This is the first study evaluating anti-CD69 therapy in a preclinical GBM model. Despite promising preclinical data in other cancers, anti-CD69 monotherapy or combination therapy with anti-PD-1 did not improve survival in this GBM model.

Drug delivery to cancer cells continues to present a major therapeutic challenge. Mesenchymal stem cells (MSCs) possess an intrinsic ability to migrate specifically to tumor tissues, making them promising candidates for targeted drug delivery. Evidence from preclinical studies indicates that MSCs loaded with therapeutic anti-cancer agents exhibit considerable anti-tumor activity. Moreover, several clinical trials are currently evaluating their effectiveness in cancer patients. The integration of MSCs with synthetic nanoparticles (NPs) enhances their therapeutic potential, particularly through the use of cell membrane-coated NPs, which represent a significant advancement in the field. This review systematically investigates the tumor microenvironment, the sources of MSCs, the tumor homing mechanisms, and the methods of loading and releasing anticancer drugs from MSCs. Furthermore, cutting-edge strategies to improve the efficacy of MSCs based drug delivery systems (DDS) including the innovative use of MSC membrane coated nanoparticles have been discussed. The study concludes with an overview of the therapeutic use of MSCs as drug carriers, including a detailed analysis of the mechanisms by which MSCs deliver therapeutics to cancer cells, enabling targeted drug delivery. It aims to elucidate the current state of this approach, identify key areas for development, and outline potential future directions for advancing MSCs based 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 © 2024 Elsevier Inc. All rights reserved.)

Interference with glycolysis metabolism not only promotes the efficient sensitization of cuproptosis, but also amplifies cytotoxic T cell functions and proliferations, thus contributing to relieve immunosuppressive tumor microenvironment. However, the synergistic mechanism and the design of multicomponent nanoformulations involving these three pathways have not yet been explored. a copper-coordinated nanoassembly (designated as Cu-GM) is reported here that integrates a lactate dehydrogenase inhibitor, galloflavin (GF), with an immune checkpoint inhibitor, myricetin (MY), to boost cancer cuproptosis-immunotherapy. These results suggest that Cu-GM can be activated by the endogenous overexpressed glutathione to release Cu + , leading to the abnormal aggregation of lipoylated proteins and iron-sulfur cluster proteins loss, which triggers proteotoxic stress and cell cuproptosis. Meanwhile, the released GF not only inhibits the glycolysis to amplify cuproptosis efficacy but also achieves effective lactate depletion, thus alleviating immunosuppressive effects of lactate. Notably, the killed tumor cells can induce immunogenic cell death to evoke the anti-tumor immunity, which further augmented by the MY-mediated immune checkpoint blockade. Taken together, the first anticancer synergy of glycolysis metabolism, cuproptosis, and immunotherapy is presented, showcasing remarkable in vivo antitumor effects and encouraging further exploration of a rational multimodal treatment approach., (© 2024 Wiley‐VCH GmbH.)

Self-assembling peptide-based materials with ordered nanostructures possess advantages such as good biocompatibility and biodegradability, superior controllability, and ease of chemical modification. Through covalent conjugation or non-covalent encapsulation, photosensitizers (PSs) can be carried by self-assembling peptide-based nanomaterials for targeted delivery towards tumor tissues. This improves the stability, solubility, and tumor accumulation of PSs, as well as reduces their dark toxicity. More importantly, these nanomaterials can be tailored with responsiveness to tumor microenvironment, which enables smart release of PSs for precise and enhanced photodynamic therapy (PDT). In this review, the self-assembly of peptide from the perspective of driving forces is first described, and various self-assembling peptide materials with zero to 3D nanostructures are subsequently highlighted for PDT of cancers in recent years. Finally, an outlook in this field is provided to motivate fabrication of advanced PDT nanomaterials., (© 2024 Wiley‐VCH GmbH.)

Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce growth differentiation factor 15 (GDF15). However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMP-activated protein kinase α1/2 (AMPKα1/2) at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma [human bladder stromal fibroblast (HBdSF) and human bladder smooth muscle cell (HBdSMC)] cells compared with normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and epithelial-to-mesenchymal transition (EMT) markers to attenuate cell proliferation and invasion of bladder cancer cells. Caffeic acid phenethyl ester (CAPE), like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMCs. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder. NEW & NOTEWORTHY This study investigates the counteraction of either CAPE or metformin with the AMPK activity increasing GDF15 expression in human bladder cells. The findings are the first study to indicate the secretion of GDF15 from cancer and stroma cells via autocrine or paracrine mechanisms. Our study suggests that GDF15, an antitumor gene in the human bladder induced by AMPK inducers, acts as a communication link between stroma and cancer cells in the human bladder.

Background: In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair)., Methods: PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models., Results: The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction., Conclusion: The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma (HCC) is a complex disease with advanced presentation that significantly affects survival rates. Therefore, novel therapeutic strategies are needed. In this study, we investigate the tumor microenvironment (TME) in HCC by analyzing 13 HCC samples at single cell level. We identified key cell populations, including CD8 + T cells, Tregs, M1/M2 macrophages, and CD4 + memory T cells, and explored their roles and interactions. Our research revealed an early enrichment of CD8 + T cells, which could potentially lead to their exhaustion and facilitate tumor progression. We also investigated the impact of percutaneous radiofrequency ablation (RFA) on the immune microenvironment. Using a dual tumor mouse model, we demonstrated that RFA induces necrosis, enhancing antigen presentation and altering immune responses. Our results indicate that RFA increases PD-L1 expression in residual liver tissue, suggesting potential immune escape mechanisms. Furthermore, the combination of RFA and anti-PD-L1 therapy in the mouse model resulted in significant improvements in immune modulation. This included increased CD8 + T cell efficacy and decreased Treg infiltration. This combination shows promise as an approach to counteract HCC progression by altering the immune landscape. This study highlights the critical interaction within the TME of HCC and suggests the possibility of improving patient outcomes by targeting immune evasion mechanisms through combined therapeutic strategies., Competing Interests: Declarations. Ethical approval: The study was also in accordance with the Helsinki Declaration and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University [No. [2024]459]. Written informed consents were obtained from all patients. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response. It comprises a complex network of stromal cells, immune cells, extracellular matrix, and blood vessels, all of which interact with cancer cells and influence tumor behaviour. This review article provides an in-depth examination of the TME, focusing on stromal cells, blood vessels, signaling molecules, and ECM, along with commonly available therapeutic compounds that target these components. Moreover, we explore the TME as a novel strategy for discovering new anti-tumor drugs. The dynamic and adaptive nature of the TME offers opportunities for targeting specific cellular interactions and signaling pathways. We discuss emerging approaches, such as combination therapies that simultaneously target cancer cells and modulate the TME. Finally, we address the challenges and future prospects in targeting the TME. Overcoming drug resistance, improving drug delivery, and identifying new therapeutic targets within the TME are among the challenges discussed. We also highlight the potential of personalized medicine and the integration of emerging technologies, such as immunotherapy and nanotechnology, in TME-targeted therapies. This comprehensive review provides insights into the TME and its therapeutic implications. Understanding the TME's complexity and targeting its components offer promising avenues for the development of novel anti-tumor therapies and improved patient outcomes.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors approved for publication. Competing interests: The authors declare that there is no conflict of interest., (© 2024. Controlled Release Society.)

Multiple strategies have been clinically employed as combination partners to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Although these combinations have demonstrated improved effectiveness in some instances, each presents its own limitations. Autophagy-targeting therapy offers several advantages when combined with ICIs, including enhanced tumor immunogenicity, reduced side effects, and broader applicability to diverse patient populations. However, emerging evidence reveals complex reciprocal regulation between autophagy and immune checkpoints which may complicate combination treatments targeting these two systems. This review focuses on the reciprocal interplay between autophagy and immune checkpoints, and provides valuable guidelines for the determination and adjustment of therapeutic regimens in the future., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) remains a daunting oncological challenge because of its aggressive nature and resistance to conventional therapies. Inhibition of the intrinsic STING pathway in GBM hampers the effectiveness of immunotherapies. To overcome this clinical limitation, a Sequential Release HydroLipo System (SRHLS) is developed, in which hydrogels and nanoparticles are combined for controlled drug release. The SRHLS sequentially released decitabine and STING agonists, thereby correcting STING signaling dysfunction through epigenetic reprogramming and enhancing antitumor immunity. According to in vitro and in vivo experiments, the SRHLS reshaped the tumor microenvironment and markedly inhibited tumor growth, recurrence, and metastasis. These findings underscore the potential of the SRHLS as a promising therapeutic strategy for GBM., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME-responsive nanoparticles (HMP1G NPs) loaded with 1-methyltryptophan (1-MT; an indoleamine 2,3-dioxygenase 1 [IDO1] inhibitor,) and S-nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1-MT-mediated ICB. The HMP1G NPs responded to H + and glutathione in the TME, releasing Mn 2+ , GSNO, and 1-MT. The released Mn 2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1-MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell-derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano-platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Photoagents with ultra-high near-infrared II (NIR-II) light energy conversion efficiency hold great promise in tumor phototherapy due to their ability to penetrate deeper tissues and minimize damage to surrounding healthy cells. However, the development of NIR-II photoagents remain challenging. In this study, an all-fused-ring quinoidal acceptor-donor-acceptor (A-D-A) molecule, SKCN, with a BTP core is synthesized, and nanoparticles named FA-SNPs are prepared. The unique quinoidal structure enhances π-electron delocalization and bond length uniformity, significantly reducing the bandgap of SKCN, resulting in strong NIR-II absorption, a high molar extinction coefficient, and a photothermal conversion efficiency of 75.14%. Enhanced molecular rigidity also facilitates efficient energy transfer to oxygen, boosting reactive oxygen species generation. By incorporating the immunomodulator R848, FA-SRNPs nanoparticles are further developed, effectively modulating the tumor immune microenvironment by reducing Tregs and M-MDSCs infiltration, promoting dendritic cell maturation, M1 macrophage polarization, and activating CD8+ T cells and NK cells. Comprehensive studies using orthotopic ovarian cancer models demonstrated strong tumor targeting, photoacoustic imaging capabilities, and significant tumor suppression and metastasis inhibition, and also showing excellent therapeutic efficacy in an orthotopic breast cancer model. This study provides strong evidence for the potential application of quinoidal A-D-A molecules in cancer photoimmunotherapy., (© 2024 Wiley‐VCH GmbH.)

In the treatment of glioma, which is one of the malignant tumors, although chemotherapy is used as the most common treatment method, it often suffers from low bioavailability. Therefore, improving the precision and efficiency of drugs is crucial in treating gliomas and a great challenge. Here, an advanced drug delivery system is reported for gliomas (CZQD@HA@DOX), which aggregates multiple features such as the susceptible imaging tracer property due to the use of CZQD and the targeting of HA to the receptor cluster 44 (CD44) of glioma cells, which provides the system with the functions of targeted enrichment and precise drug delivery at the tumor site. The pH-responsive drug delivery system has not only an excellent encapsulation rate but also a high drug loading capacity, and the doxorubicin loaded on it can be released centrally at the tumor microenvironment site and causes an increase of reactive oxygen species in the mitochondria and trigger oxidative stress, which leads to high expression of Bax apoptotic proteins, ultimately activating the mitochondrial pathway-mediated apoptotic process in glioma cells. Overall, this drug delivery system has great potential for application in precision targeted therapy and visual tracer imaging of gliomas., (© 2024 Wiley‐VCH GmbH.)

The notorious tumor microenvironment (TME) usually becomes more deteriorative during phototherapeutic progress that hampers the antitumor efficacy. To overcome this issue, we herein report the ameliorative and adaptive nanoparticles (TPASIC-PFH@PLGA NPs) that simultaneously reverse hypoxia TME and switch photoactivities from photothermal-dominated state to photodynamic-dominated state to maximize phototherapeutic effect. TPASIC-PFH@PLGA NPs are designed by incorporating oxygen-rich liquid perfluorohexane (PFH) into the intraparticle microenvironment to regulate the intramolecular motions of AIE photosensitizer TPASIC. TPASIC exhibits a unique aggregation-enhanced reactive oxygen species (ROS) generation feature. PFH incorporation affords TPASIC the initially dispersed state, thus promoting active intramolecular motions and photothermal conversion efficiency. While PFH volatilization leads to nanoparticle collapse and the formation of tight TPASIC aggregates with largely enhanced ROS generation efficiency. As a consequence, PFH incorporation not only currently promotes both photothermal and photodynamic efficacies of TPASIC and increases the intratumoral oxygen level, but also enables the smart photothermal-to-photodynamic switch to maximize the phototherapeutic performance. The integration of PFH and AIE photosensitizer eventually delivers more excellent antitumor effect over conventional phototherapeutic agents with fixed photothermal and photodynamic efficacies. This study proposes a new nanoengineering strategy to ameliorate TME and adapt the treatment modality to fit the changed TME for advanced antitumor applications., 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.)

Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting in down-regulation of target functional genes. AUY922 additionally altered the tumor microenvironment (TME) into an inflamed state with increased cytokine production in T cells, including interferon gamma, granzyme B, and perforin, and inhibited M2 polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Additionally, our results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jaffer Ajani reports financial support was provided by National Institutes of Health. Jaffer Ajani reports financial support was provided by US Department of Defense. none If there are other authors, they 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.)

Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu 2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half-life of ES by membrane-coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non-specific ES release. After internalization, ECNM dissociates via the glutathione-responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Radiotherapy as a mainstay of in-depth cervical cancer (CC) treatment suffers from its radioresistance. Radiodynamic therapy (RDT) effectively reverses radio-resistance by generating reactive oxygen species (ROS) with deep tissue penetration. However, the photosensitizers stimulated by X-ray have high toxicity and energy attenuation. Therefore, X-ray responsive diselenide-bridged mesoporous silica nanoparticles (DMSNs) are designed, loading X-ray-activated photosensitizer acridine orange (AO) for spot blasting RDT like Trojan-horse against radio-resistance cervical cancer (R-CC). DMSNs can encapsulate a large amount of AO, in the tumor microenvironment (TME), which has a high concentration of hydrogen peroxide, X-ray radiation triggers the cleavage of diselenide bonds, leading to the degradation of DMSNs and the consequent release of AO directly at the tumor site. On the one hand, it solves the problems of rapid drug clearance, adverse distribution, and side effects caused by simple AO treatment. On the other hand, it fully utilizes the advantages of highly penetrating X-ray responsive RDT to enhance radiotherapy sensitivity. This approach results in ROS-induced mitochondria damage, inhibition of DNA damage repair, cell cycle arrest and promotion of cancer cell apoptosis in R-CC. The X-ray responsive DMSNs@AO hold considerable potential in overcoming obstacles for advanced RDT in the treatment of R-CC., 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 Ltd.)

Gynecological tumors, such as ovarian, endometrial, and cervical cancers, alongside breast cancer, represent significant malignancies that pose serious threats to women's health worldwide. Standard treatments, including surgery, chemotherapy, radiotherapy, and targeted therapies, are commonly utilized in clinical practice. However, challenges such as high recurrence rates, drug resistance, and adverse side effects underscore the urgent need for more effective therapeutic options. Osthole, a natural coumarin compound derived from Chinese herbal medicine, has demonstrated remarkable antitumor activity against various cancers. Emerging evidence indicates that osthole can inhibit the proliferation, invasion, and metastasis of gynecological and breast cancer cells through various mechanisms, including inducing apoptosis and autophagy, regulating the tumor microenvironment, inhibiting tumor angiogenesis, and enhancing the sensitivity of cancer cells to chemotherapy and radiotherapy. This review highlights the recent advancements in osthole research within the context of gynecological and breast cancers, focusing on its molecular mechanisms, and offers a theoretical foundation for its potential development as an anticancer agent., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Other declarations: The figure was created using Adobe Illustrator 2024 (v28.0; Adobe Inc.), (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)