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Owing to the desmoplastic stroma constituted by cancer-associated fibroblasts (CAFs), few immune cells infiltrate the pancreatic ductal adenocarcinoma (PDAC). Gabapentin can impede the production of ketoacids by CAFs to support cancer cells. However, in our study, we discovered a dose-dependent increase in transforming growth factor β1 (TGF-β1) levels in cancer cells in response to gabapentin. This reverse increase of TGF-β1 contributes to 'Gabapentin-resistance', leading to the antitumor effects on PDAC cell lines are negatively negotiated in the presence of pancreatic stellate cells. Pirfenidone synergistically inhibited the growth and apoptosis resistance of PDAC when combined with Gabapentin. In a mouse orthotopic PDAC model, Fe 3+ -mediated coordination nanodrugs, which contain gabapentin, pirfenidone and the natural polyphenol (EGCG), efficiently promoted the infiltration of naïve CD8 + T cells (CD44 low CD62L high ) and the accumulation of inflammatory CAFs (α-SMA low IL-6 high ). This led to a nearly two-fold increase in survival compared to the control. Furthermore, we identified a new subpopulation as Hmox1 high iCAFs following treatment with our nanodrugs. Hmox1 high iCAFs overexpressed the Cxcl10 receptor (Sdc4) and facilitated functional CD8 + T-cell infiltration through the Tnfsf9-Tnfrsf9 axis. Overall, our nanodrugs reshape the phenotype of CAFs and enhance functional CD8 + T-cell infiltration into tumors, holding the potential to be a safe and promising therapy for PDAC., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Three-dimensional (3D) tumor microdevices are promising platform for biomimetic antitumor prediction and high-throughput chemotherapeutic screening and play crucial roles in the exploration of cancer-associated pharmaceutics and therapeutics. Traditional cell manipulation tools (e.g., non-adhesive surfaces and hanging drops) and recent microengineered systems (e.g., microfluidic chips and micropatterned array chips) have progressed in terms of microscale control, substantial tumor production, programmable drug combinations, and throughput analysis. However, establishing a facile 3D tumor microdevice to construct heterotypic tumor-microenvironmental profiles and for throughput, implementable, multi-instrument-compatible analysis of chemotherapies to advance consumer-grade tumor modelling tools is still being explored., Results: In this study, we present a facilely operated tumor-on-a-chip platform for massive production of heterotypic 3D tumors and diverse investigations of combinatorial chemotherapy screening. Large quantity of heterotypic tumor generation with high geometric controllability (size difference: 19.6 μm) and operational repeatability (n = 10) was achieved using simple-to-fabricate micropatterned chips. Multiple characteristics of solid tumors, including phenotypic gradients (viability and proliferation) and heterogeneous cellular compositions (multi-cell participation and stroma composition), were reproduced in heterotypic tumors, being more biomimetic than homotypic tumors. We completed the user-friendly analytical evaluation of individual and combinatorial drug therapies, and demonstrated the high applicability of the platform in biomimetic tumor-related large-scale manipulation and on-chip analysis, as well as its high compatibility for off-chip detection. The entire operative process during tumor production and chemotherapy only requires the routine and easy-to-master pipetting manipulation., Significance: The establishment of a biomimetic and easy-to-use 3D tumor platform and the large-scale screening-like evaluation of combinatorial chemotherapies based on the usage of the micropatterned chip was achieved in a user-friendly manner. This advancement has significant application potential in the fields of oncology, drug discovery, and tissue engineering, and is expected to be valuable for developing accessible and generalizable tumor-on-a-chip microsystems for exploring 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gastric cancer stem cells (GCSCs) are key contributors to tumorigenesis, recurrence and metastasis, complicating gastric cancer (GC) treatment. Rhaponticin (RA), a potential novel anticancer drug, has unexplored effects on GCSCs., Methods: GCSCs were isolated using CD133 and CD166 markers with magnetic bead separation method and then evaluated their response to the IC50 concentrations of RA (16.90 µg/mL for BGC-823 and 22.18 µg/mL for SGC-7901), and effects on cell proliferation, migration, invasion, and stemness were measured. We analyzed the GCSC-related microarray dataset GSE111556 and explored RA's role in restoring programmed cell death ligand 1 (PD-L1) function in CD133+/CD166 + cells post-PD-L1 knockdown. RA's impact on tumour growth and immune microenvironment was assessed in a xenograft mouse model., Results: The CD133+/CD166 + subpopulation exhibited stem-like characteristics, with the highest proportion in BGC-823 (38.85%) and SGC-7901 (43.81%) cells. These cells formed tumour spheres and had increased expression of stemness markers Sox2 and Oct-4 (compared to the parental cell line, P < 0.001). RA treatment showed no toxicity to normal GES-1 cells but reduced the viability of CD133+/CD166 + cells in a dose-dependent manner, with IC50 values of 16.90 µg/ml for BGC-823 and 22.18 µg/ml for SGC-7901. RA also decreased the proportion of CD133+/CD166 + cells and their stem-like properties (P < 0.001). Analysis of the GEO database identified PD-L1 as a key target gene of RA, with high expression in GC tissues. Knocking down PD-L1 in CD133+/CD166 + cells and introducing RA did not significantly change PD-L1 expression (P>0.05), suggesting RA's effect may be PD-L1 dependent. In a xenograft mouse model, the tumour size in the RA treatment group was approximately one-sixth that of the CD133+/CD166 + group (P < 0.001). Post-RA treatment, there was an elevation in the expression levels of CD4 and CD8, alongside a reduction in PD-L1 expression (P < 0.001)., Conclusions: RA suppresses GCSC stem - like phenotype by inhibiting PD - L1 and enhancing T cell tumour infiltration in the studied models. These findings suggest that RA may have potential for further exploration as a candidate for GC treatment, but extensive preclinical and clinical studies are required to determine its true therapeutic value., Competing Interests: Declarations. Ethical approval: Animal experiments were approved and supervised by the animal ethics committee of Shaanxi Provincial People’s Hospital. This study adheres to relevant ethical and operational standards to ensure that animals are properly cared for and protected during the experimental process. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

M2-type macrophages (M2Φ) play a pro-tumorigenic role and are closely associated with tumor development, where metabolic dysregulation exacerbates the immunosuppressive tumor microenvironment and fosters tumor growth. Mitochondria serve as the regulatory center of cellular metabolism, yet effective methods to modulate M2Φ mitochondria within the tumor microenvironment remain lacking. In this study, we developed a technique utilizing the bio-encapsulation of mitochondria in Zeolitic Imidazolate Framework-8 (ZiF-8), referred to as Mito@ZiF-8. Our findings demonstrated that this coating protects intact mitochondria and preserves their bioactivity over an extended period after isolation. We successfully delivered Mito@ZiF-8 into M2Φ, which inhibited the secretion of pro-inflammatory factors, promoted the release of anti-inflammatory factors, and reprogrammed M2Φ metabolism. This innovative approach has the potential to reduce breast cancer cell metastasis and enhance sensitivity to chemotherapy drugs such as 6-thioguanine, cisplatin, and doxorubicin (Dox). Mito@ZiF-8 aims to reprogram the M2Φ microenvironment to support anti-tumor therapies, offering a novel strategy for improving the effectiveness of breast cancer treatment.

Fibrinolysis influences the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM). Here we show that activation of plasmin, a key fibrinolytic agent, by annexin A2 (ANXA2) distinctly impacts progression of BCR-ABL1 + B-cell acute lymphoblastic leukemia (B-ALL) via modulation of the extracellular matrix (ECM) in the BMM. The dense ECM in a BMM with decreased plasmin activity entraps insulin-like growth factor (IGF) 1 and reduces mTORC2-dependent signaling and proliferation of B-ALL cells. Conversely, B-ALL conditions the BMM to induce hepatic generation of plasminogen, the plasmin precursor. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, reduces tumor burden and prolongs survival, including in xenogeneic models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Gastric cancer (GC) is the fifth most common cancer worldwide, particularly prevalent in Asia, especially in China, where both its incidence and mortality rates are significantly high. Meanwhile, nanotechnology has demonstrated great potential in the treatment of GC. In particular, nanodrug delivery systems have improved therapeutic efficacy and targeting through various functional modifications, such as targeting peptides, tumor microenvironment responsiveness, and instrument-based methods. For instance, silica (SiO 2 ) has excellent biocompatibility and can be used as a drug carrier, with its porous structure enhancing drug loading capacity. Polymer nanoparticles regulate drug release rates and mechanisms by altering material composition and preparation methods. Lipid nanoparticles efficiently encapsulate hydrophilic drugs and promote cellular uptake, while carbon-based nanoparticles can be used in biosensors and drug delivery. Targets such as integrins, HER2 receptors, and the tumor microenvironment have been used to improve drug efficacy in GC treatment. Nanodrug delivery techniques not only enhance drug efficacy and delivery capabilities but also selectively target tumor cells. Currently, there is a lack of systematic summarization and synthesis regarding the relationship between nanodrug delivery systems and GC treatment, which to some extent hinders researchers and clinicians from efficiently searching for and referencing related studies, thereby reducing work efficiency. This study aims to systematically summarize the existing research on the relationship between nanodrug delivery systems and GC treatment, making it easier for professionals to search and reference, and thereby promoting further research on the role of nanodrug delivery systems and their clinical applications in GC. This review discusses the applications of functionalized nanocarriers in the treatment of GC in recent years, including surface modifications with targeted markers, the combination of phototherapy, chemotherapy, and immunotherapy, along with their advantages and challenges. It also examines the future prospects of targeted nanomaterials in GC treatment. The review particularly focuses on the combined application of nanocarriers in multiple treatment modalities, such as phototherapy, chemotherapy, and immunotherapy, demonstrating their potential in multimodal treatments. Furthermore, it thoroughly explores the specific challenges that nanocarriers face in GC treatment, such as biocompatibility, drug release control, and clinical translation issues, while providing a systematic outlook on future developments. Additionally, this study emphasizes the potential value and feasibility of nanocarriers in clinical applications, contrasting with most reviews that focus on basic research. Through these innovations, we offer new perspectives and directions for the development of nanotechnology in the treatment of GC., Competing Interests: Declarations. Ethics statement: Not applicable. Competing interests: The authors declare no competing interests. Search strategy: The search was conducted on PubMed using the keywords "Nanocarriers" and "GC." Subsequently, each search result was systematically reviewed to ensure its relevance to Nanocarriers and GC. Only studies aligned with this topic were included in the literature review for further analysis and discussion, while others were excluded., (© 2024. The Author(s).)

Efficient retention of drugs at tumor sites was always desirable to maximize therapeutic functions, yet the main concern is the dynamic blood clearance induced fast removal from localized lesion. Herein, a tumor microenvironment activated covalently conjugation (self- and proximal conjugation) of tyramine modified Pt nanoclusters (PCMT NPs) was constructed by in situ produced radical hooks, leading to efficient accumulation of PCMT NPs at tumor sites. Such accumulation further aggravated the oxidative stress and provoked autophagy of tumor cells via activating the caspase-3 pathway mediated massive apoptosis, thereby stimulating immunogenic cell death (ICD). As verified by in vivo results, the PCMT NPs effectively suppressed primary and distant tumor growth (with an inhibition rate of 99%) while eliciting immunotherapeutic responses. As such, a new paradigm for boosting drug retention was provided, which enabled specific tumor treatment with synergistic therapeutic outcomes.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy., Competing Interests: Declaration of interests C.D. reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group, and grants from BMBF to the institution during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca and Molecular Health, grants from Myriad, personal fees from Merck, and other funding from Sividon Diagnostics outside the submitted work; in addition, C.D. has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1—cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1—therapy response issued. J.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). Funding was also received (non-financial/medical writing) from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has royalties in VM Scope and patents pending: EP14153692.0, EP21152186.9, and EP15702464.7. T.K. reports a patent WO2020109570A1 pending. S.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). J.H. reports research funding from Lilly; honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, Seagen, Gilead, and Daiichi; consulting and advisory relationships with Lilly, Novartis, Roche, Pfizer, AstraZeneca, Gilead, and Daiichi; travel expenses from Roche, Novartis, Daiichi, and Gilead. P.J. reports research funding and travel expenses from Gilead Sciences GmbH. C.H. reports an advisory role and speakers bureau role for AstraZeneca, Roche, Novartis, and Aristo Pharma. B.V.S. is an employee of BioNTech SE and reports a patent WO2020109570A1 pending. J.-U.B. reports consultation fees, honoraria, and reimbursement for attending symposia from AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen. M.v.M. reports personal fees, honoraria, or travel grants from Amgen, AstraZeneca, Daiichi Sankyo, Genomic Health, GSK, Lilly, Molecular Health, MSD, Mylan, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen. C. Schem reports speaker activities for Roche, Pfizer, Novartis, Celgen, Novartis, Exact Sciences, MSD, AstraZeneca, Lilly, and Seagen, as well as advisory boards for Roche, Astra Zeneca, Pfizer, Novartis, MSD, Amgen, Exact Sciences, Stemline, Lilly, and Novartis. T.L. reports personal fees from Amgen, Roche, Teva, Clovis, Tesaro, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, AstraZeneca, Daiichi Sankyo, Stemline, and Seagen outside of the submitted work. T.L. participates in advisory boards from Amgen, MSD, Tesaro, Roche, Pfizer, Lilly, Myriad, Esai, GSK, Gilead, Daiichi Sankyo, Roche, and AstraZeneca outside of the submitted work and T.L. received travel support from Pfizer, PharmaMar, MSD, Celgene, Roche, AstraZeneca, Gilead, Daiichi Sankyo, Stemline, and Clovis outside of the submitted work. P.S. reports grants, personal fees, and non-financial support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Company, MSD, Incyte, Janssen-Cilag, Novartis, Takeda, Pfizer, and Roche. V.M. received speaker honoraria from AstraZeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, and Pierre Fabre; consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, and Stemline; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, Daiichi Sankyo, and Gilead. L.P. has received consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, and Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb. C.E.G. reports the following competing interests: Exact Sciences, Advisory Board, personal; AbbVie, Steering Committee member, institutional, co-chair of SC for BrighTNess; Daiichi Sankyo, member SC, institutional, co-chair of SC for DESTINY-Breast05; Genentech/Roche, SC member, institutional, co-chair of SC for lidERA; Genentech/Roche, coordinating PI, institutional, NSABP B-59/GeparDouze; and Genentech/Roche, SC member, institutional, co-chair of SC for KATHERINE. C.J. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Seagen, Gilead, and Novartis and has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lilly, Stemline, and Medac. V.N. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Novartis, Pfizer, and Roche (paid to the institution). GBG Forschungs GmbH received other funding from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has the following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and VM Scope GmbH. M.U. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead, and Novartis; has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lily, Stemline, Genzyme, and Medac; and all honoraria and fees are paid to the employer/institution. S.L. reports grants and other funding from AbbVie; other funding from Amgen; grants and other funding from AstraZeneca; other funding from BMS; grants and other funding from Celgene; grants, non-financial support, and other funding from Daiichi Sankyo; other funding from EirGenix; other funding from Eisai Europe Ltd; other funding from GSK; grants, non-financial support, and other funding from Immunomedics/Gilead; other funding from Lilly; other funding from Merck; grants from Molecular Health; grants, non-financial support, and other funding from Novartis; grants, non-financial support, and other funding from Pfizer; other funding from Pierre Fabre; other funding from Relay Therapeutics; grants, non-financial support, and other funding from Roche; other funding from Sanofi; non-financial support and other funding from Seagen; and other funding from Olema Pharmaceuticals, outside the submitted work. In addition, S.L. has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer nanovaccines have emerged as an indispensable weapon for tumor treatment. However, insufficient immunogenicity and immunosuppression hamper the therapeutic effects of nanovaccines. Here, biodegradable nanovaccines (OMPP) composed of ovalbumin (OVA)-manganese oxide nanoparticles, amphiphilic poly(γ-glutamic acid) (γ-PGA), and ε-polylysine (PL) are constructed to realize enhanced cancer immunotherapy. Interestingly, amphiphilic γ-PGA and PL could serve as both carriers and immunoadjuvants to promote the cytosolic delivery of antigens and enhance the maturation of dendritic cells. Additionally, taking advantage of the photothermal property of OMPP, immunogenic cell death and in situ release of tumor-associated antigens can be triggered under near-infrared light irradiation for personalized tumor treatment. Moreover, OMPP nanovaccines can efficiently alleviate tumor hypoxia and downregulate programmed death-ligand 1 expression to reprogram the immunosuppressive tumor microenvironment. OMPP-mediated therapy has been shown to provoke robust immune responses to suppress B16-OVA melanoma and prevent postsurgical tumor recurrence. This work presents a facile strategy for the fabrication of nanovaccines by integrating carrier and adjuvant while exploring the inherent properties to promote antigen release and modulate immunosuppression, which demonstrates great potential for effective cancer immunotherapy.

Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR). Interestingly, these differ by breast cancer receptor subtype. Measures of the spatial distributions of immune cells within the tumor microenvironment, in particular colocalization or close spatial proximity of PD-1 + T cells with PD-L1 + cells (immune and tumor cells), are significantly associated with response in the overall cohort as well as the in the triple negative (TN) and HR + HER2 - subtypes. Our findings indicate that biomarkers associated with immune cell signaling, immune cell densities, and spatial metrics are predictive of neoadjuvant ICB efficacy in breast cancer., Competing Interests: Declaration of interests J.W. reports honoraria from DAVA Oncology; consults for Baylor College of Medicine; has ownership in Theralink; and is co-inventor of the RPPA technology, and phospho-HER2 and -EGFR response predictors with filed patents. C.H. is an employee of Akoya Biosciences. R.N. reports grants from Quantum Leap, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics outside the submitted work; and personal fees from Aduro, AstraZeneca, Athenex, Celgene, Daiichi Sankyo, G1 Therapeutics, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, and Syndax. M.C.L. reports support from Eisai, Genentech, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro. D.Y. reports unrelated support from Boehringer Ingelheim. A.M.D. reports honoraria or consulting for Pfizer and Context Therapeutics and reports support from Novartis, Pfizer, Genentech, Calithera, and Menarini. L.P. reports consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, and Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol-Myers Squibb. D.A.B. is co-owner of Berry Consultants LLC, a company that designs adaptive clinical trials (including I-SPY2). E.F.P. reports leadership, stock/ownership, consulting/advisory, and travel funds from Perthera and Ceres Nanosciences; stock and consulting/advisory for Theralink Technologies, Inc; support from Ceres Nanosciences, GlaxoSmithKline, AbbVie, Symphogen, Genentech, SpringWorks Therapeutics, and Deciphera Therapeutics; and patents/royalties from NIH and filed patents for p-HER2 and p-EGFR response predictors. L.v.V. is a co-inventor of the MammaPrint signature and a part-time employee and stockholder of Agendia NV. L.E. is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative (QLHC), has received grant support from QLHC for the I-SPY2 trial, and is on the Blue Cross/Blue Shield Medical Advisory Panel., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H 2 O 2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H 2 O 2 is generated during this procedure, which can endogenously replenish the consumed H 2 O 2 . Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H 2 O 2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Cancer is becoming the main public health problem globally. Conventional chemotherapy approaches are slowly being replaced or complemented by new therapies that avoid the loss of healthy tissue, limit off-targets, and eradicate cancer cells. Immunotherapy is nowadays an important strategy for cancer treatment, that uses the host's anti-tumor response by activating the immune system and increasing the effector cell number, while, minimizing cancer's immune-suppressor mechanisms. Its efficacy is still limited by poor therapeutic targeting, low immunogenicity, antigen presentation deficiency, impaired T-cell trafficking and infiltration, heterogeneous microenvironment, multiple immune checkpoints and unwanted side effects, which could benefit from improved delivery systems, able to release immunotherapeutic agents to tumor microenvironment and immune cells. Nanoparticles (NPs) for immunotherapy (Nano-IT), have a huge potential to solve these limitations. Natural and/or synthetic, targeted and/or stimuli-responsive nanoparticles can be used to deliver immunotherapeutic agents in their native conformations to the site of interest to enhance their antitumor activity. They can also be used as co-adjuvants that enhance the activity of IT effector cells. These nanoparticles can be engineered in the natural context of cell-derived extracellular vesicles (EVs) or exosomes or can be fully synthetic. In this review, a detailed SWOT analysis is done through the comparison of engineered-synthetic and naturaly-derived nanoparticles in terms of their current and future use in cancer immunotherapy.

Despite demonstrating promising outcomes in treating hematologic malignancies, the efficacy of chimeric antigen receptor-modified T (CAR-T) cell therapy remains limited when applied to solid tumors due to tumor immune microenvironment (TIME). Strategies to augment CAR-T cell efficacy against solid tumors have been investigated by ameliorating TIME to a certain extent. In this study, Cabozantinib was utilized in combination with CAR-T cells targeting carbonic anhydrase IX (CAIX) for the treatment of renal cancer. Our findings indicate that combination therapy with CAIX-CAR-T and Cabozantinib demonstrated synergistic efficacy against an orthotopic xenograft tumor model and a subcutaneous tumor model of renal cell carcinoma in mice. Mechanistically, it was observed that CAR-T cells combined with Cabozantinib led to an increase in the infiltration of tumor-infiltrating T cells, while reducing tumor-associated macrophages and M2 polarization. Additionally, Cabozantinib blocked the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis by decreasing the expression of PD-L1 in tumor cells and PD-1 in T cells. Furthermore, Cabozantinib promoted CAR-T cell effector function and reduced T cell exhaustion. This combination therapy represents a novel approach to enhancing CAR-T cell efficacy against solid tumors and holds significant promise for advancing CAR-T cell therapy in clinical settings., 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.)

Cancer, a deadly and constantly evolving disease, has always been difficult to treat due to the complexity of the tumor microenvironment (TME). Cancer nanomedicines are proving to be a much better alternative for treatment due to their stability and ability to provide an efficient targeted therapy. An amorphous alloy bimetallene with an introduction of 2 % tensile strain with photothermal multiple enzyme-like catalytic activity is being presented here that functions as a TME-responsive nanozyme. Labeled as RhRu, this bimetallene, under acidic conditions, functions as oxidase (OXD) - like, peroxidase (POD) - like and catalase (CAT) - like enzymes, by producing radicals and disrupting the tumor cells. This effect is enhanced especially upon irradiation of laser and introduction of tensile strain in its heterophase boundaries. This current highlight discusses the strain engineering tactic of la-RhRu bimetallene and its potency as an anti-tumor therapeutic., (© 2024 Wiley-VCH GmbH.)

Introduction: Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by elevating intracellular iron levels or inhibiting glutathione peroxidase 4 (GPX4) activity. However, the intracellular antioxidative defense mechanisms endow tumor cells with ferroptosis resistance capacity. The purpose of this study was to develop a synergistic therapeutic platform to enhance the efficacy of ferroptosis-based tumor therapy., Methods: In this study, a multifunctional nano-catalytic therapeutic platform (mFeB@PDA-FA) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) was developed to effectively trigger ferroptosis in tumor. In our work, iron-based mesoporous Fe 3 O 4 nanoparticles (mFe 3 O 4 NPs) were employed for the encapsulation of L-buthionine sulfoximine (BSO), followed by the modification of folic acid-functionalized polydopamine (PDA) coating on the periphery. Then, the antitumor effect of mFeB@PDA-FA NPs was evaluated using Human OS cells (MNNG/HOS) and a subcutaneous xenograft model of osteosarcoma., Results: mFe 3 O 4 harboring multivalent elements (Fe 2+/3+ ) could catalyze hydrogen peroxide (H 2 O 2 ) into highly cytotoxic ˙OH, while the tumor microenvironment (TME)-responsive released BSO molecules inhibit the biosynthesis of GSH, thus achieving the deactivation of GPX4 and the enhancement of ferroptosis. Moreover, thanks to the remarkable photothermal conversion performance of mFe 3 O 4 and PDA shell, PTT further synergistically enhanced the efficacy of CDT and facilitated ferroptosis. Both in vivo and in vitro experiments confirmed that this synergistic therapy could achieve excellent tumor inhibition effects., Conclusion: The nanotherapeutic platform mFeB@PDA-FA could effectively disrupted the redox homeostasis in tumor cells for boosting ferroptosis through the combination of CDT, PTT and GSH elimination, which provided a new perspective for the treatment of ferroptosis sensitive tumors., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Song et al.)

As an important innate immune cell in the body, macrophages have a strong ability to phagocytic tumor cells and maintain the innate immune response. Tumor-associated macrophages play a more prominent role in regulating tumor immunity and are currently an important target of antitumor immunity. As a new type of antitumor therapy, tumor immunotherapy has great potential, combined chemotherapy, targeting and other therapeutic means can significantly enhance the antitumor therapy effect. At present, a number of natural products have been proved to have significant immunomodulatory and antitumor effects, and have become a hot field of antitumor immunity research. Studies have found that a variety of natural products, such as polysaccharides, flavonoids, saponins, lactones, and alkaloids, can induce the polarization of M1 macrophages, inhibit the polarization of M2 macrophages, and regulate the expression of immune-related cytokines by targeting specific signaling pathways to enhance the killing effect of macrophages on tumor cells and improve the tumor immune microenvironment, and finally better play the antitumor immune function. In this paper, by summarizing the research results of the specific mechanism of natural products targeting tumor-associated macrophages to exert antitumor immunity in recent years, we discussed the aspects of natural products targeting tumor-associated macrophages to enhance antitumor immunity, in order to provide a new research idea for tumor immunotherapy and further improve the effectiveness of clinical antitumor therapy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Achieving selective and durable inhibition of programmed death ligand 1 (PD-L1) in tumors for T cell activation remains a major challenge in immune checkpoint blockade therapy. We herein presented a set of clickable inhibitors for spatially confined PD-L1 degradation and radioimmunotherapy of cancer. Using metabolic glycan engineering click bioorthogonal chemistry, PD-L1 expressed on tumor cell membranes was labeled with highly active azide groups. This enables covalently binding of the clickable inhibitor with PD-L1 and subsequent PD-L1 degradation. A pH-activatable nanoparticle responding to extracellular acidic pH of tumor was subsequently used to deliver the clickable PD-L1 inhibitor into extracellular tumor microenvironment for depleting PD-L1 on the surface of tumor cell and macrophage membranes in vivo. We further demonstrated that a combination of the clickable PD-L1 inhibitor with radiotherapy (RT) eradicated the established tumor by inhibiting RT-up-regulated PD-L1 in the tumor tissue. Therefore, selective PD-L1 blockade in tumors via the clickable PD-L1 inhibitor offers a versatile approach to promote cancer immunotherapy.

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834., (©2024 American Association for Cancer Research.)

A variety of state-of-the-art nanovaccines (NV) combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T-cell infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the TME need to be explored to enhance the activity of NVs. Here, we developed photo-enhanceable inflammasome-activating NVs (PIN) to achieve precise in situ delivery of a tumor antigen and a hydrophobic small molecule activating the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome (NLRP3) pathway. Near-infrared light irradiation promoted PIN accumulation in tumor sites through photo-triggered charge reversal of the nanocarrier. Systematic PIN administration facilitated intratumoral NLRP3 inflammasome activation and antigen cross-presentation in antigen-presenting cells upon light irradiation at tumor sites. Furthermore, PIN treatment triggered immune responses by promoting the production of proinflammatory cytokines and activating antitumor immunity without significant systematic toxicity. Importantly, the PIN enhanced the efficacy of immune checkpoint blockade and supported the establishment of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Collectively, this study reports a safe and efficient photoresponsive system for codelivery of antigens and immune modulators into tumor tissues, with promising therapeutic potential. Significance: The development of a photoresponsive nanovaccine with spatiotemporal controllability enables robust tumor microenvironment modulation and enhances the efficacy of immune checkpoint blockade, providing an effective immunotherapeutic strategy for cancer treatment. See related commentary by Zhen and Chen, p. 3709., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial., Experimental Design: Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients., Results: The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples., Conclusions: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy., (©2024 American Association for Cancer Research.)

Metformin is an attractive candidate drug among all the repurposed drugs for cancer. Extensive preclinical and clinical research has evaluated its efficacy in cancer therapy, revealing a mixed outcome in clinical settings. To fully exploit metformin's therapeutic potential, understanding cellular factors relevant to its transport and accumulation in cancer cells needs to be understood. This review highlights the relevance of metformin transporter status towards its anti-cancer potential. Metformin transporters are regulated at pre-transcriptional, transcriptional, and post-translational levels. Moreover, the tumour microenvironment can also influence metformin accumulation in cancer cells. Also, Metformin treatment can regulate its transporters by altering global DNA methylation, protein acetylation, and transcription factors. Importantly, metformin transporters not only influence chemotherapeutic drug toxicity but are also associated with the prognosis and survival of individuals having cancer. Strategic decisions based on the expression and regulation of metformin transporters holds promise for its therapeutic implications and relevance., 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.)

TGF-β is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-β signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-β to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-β can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-β is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-β receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-β signaling via receptor blockade and it did not arouse TGF-β legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-β secretion and inhibited myCAFs viability marked by α-SMA and FAPα. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the α-SMA + / FAPα + myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-β protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-β inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-β signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-β related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic 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 © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the "gut-brain" axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients., 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.)

Traditional hepatocellular carcinoma-chip models lack the cell structure and microenvironments necessary for high pathophysiological correlation, leading to low accuracy in predicting drug efficacy and high production costs. This study proposed a decellularized hepatocellular carcinoma-on-a-chip model to screen anti-tumor nanomedicine. In this model, human hepatocellular carcinoma (HepG2) and human normal liver cells (L02) were co-cultured on a three-dimensional (3D) decellularized extracellular matrix (dECM) in vitro to mimic the tumor microenvironments of human hepatocellular carcinoma in vivo. Additionally, a smart nanomedicine was developed by encapsulating doxorubicin (DOX) into the ferric oxide (Fe 3 O 4 )-incorporated liposome nanovesicle (NLV/Fe+DOX). NLV/Fe+DOX selectively killed 78.59% ± 6.78% of HepG2 cells through targeted delivery and synergistic chemo-chemodynamic-photothermal therapies, while the viability of surrounding L02 cells on the chip model retained high, at over 90.0%. The drug efficacy tested using this unique chip model correlated well with the results of cellular and animal experiments. In summary, our proposed hepatocellular carcinoma-chip model is a low-cost yet accurate drug-testing platform with significant potential for drug screening., 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.)

In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 ± 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC 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.)

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Babaodan (BBD) is a unique Chinese medication utilized in traditional Chinese medicine. It can eliminate toxins, induce diuresis, and eliminate yellowish hue. In addition to treating acute and chronic viral hepatitis, cholecystitis, cholangitis, and urinary tract infections, BBD has garnered popularity as a substitution treatment for several malignant cancers, particularly hepatocellular carcinoma (HCC)., Aim of the Study: To elucidate the efficacy and mechanism of BBD alone and combined with camrelizumab (CLM) for treating HCC., Methods: We investigated the effects of BBD on the HCC tumor microenvironment in vivo. Furthermore, we evaluated its effects on tumor growth and metastasis induced by M2 macrophages in vitro., Results: In a mouse model of orthotopic HCC, BBD decreased tumor growth. Furthermore, it increased the M1/M2 macrophage ratio and CD8 + T-cell abundance in mice. In addition, BBD reversed HCC cell proliferation and metastasis induced by M2 macrophages, increased the anti-HCC effect of low-dose CLM, and attenuated organ damage induced by high-dose CLM. Lastly, BBD enhanced the efficacy of CLM via the PI3K/AKT/mTOR signaling pathway., Conclusion: BBD increases the antitumor effect of CLM by modulating the tumor immune microenvironment and attenuating its the toxic side effects of CLM., 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.)

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. In this study, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemoimmunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance in more than 60% of patients with TNBC. Development of a mAb capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating Toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90% to 100% in animal studies. Single-cell RNA sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemoimmunotherapy for TNBC. Significance: An anti-CD276 monoclonal antibody conjugated with both a cytotoxic drug and an immune boosting reagent effectively targets triple-negative breast cancer by inducing tumor cell death and stimulating immune cell infiltration., (©2024 The Authors; Published by the American Association for Cancer Research.)

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through "starvation therapy", cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H 2 O 2 ). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H 2 O 2 , while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors have given their consent for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The clinical efficacy of cancer vaccines is closely related to immunoadjuvants that play a crucial role in magnifying and prolonging the immune response. Muramyl dipeptide (MDP), a minimal and conserved peptidoglycan found in almost all bacteria, can trigger robust immune activation by uniquely antagonizing the nucleotide-binding oligomerization domain 2 (NOD2) pathway. However, its effectiveness has been hindered by limited solubility, poor membrane penetration, and rapid clearance from the body. Here, we introduce MDP-presenting polymersomes as artificial nanobacteria (NBA) to boost the antitumor immune response. The NBA, featuring abundant MDP molecules, induces superior stimulation of immune cells including macrophages and bone marrow-derived dendritic cells (BMDCs) compared to free MDP, likely via facilitating immune cell uptake and cooperatively stimulating systemic NOD2 signaling. Importantly, systemic administration of NBA significantly enhances the chemo-immunotherapy of B16-F10 melanoma-bearing mice pretreated with doxorubicin by reversing the immunosuppressive tumor microenvironment. Furthermore, NBA carrying ovalbumin and B16-F10 cell lysates induces robust OVA-IgG antibody production and effectively inhibit tumor growth, respectively. The artificial nanobacteria hold great promise as a potent systemic immunoadjuvant for cancer immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically "cold" PDAC into "hot" is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.

Recently, the emerging chemotherapy (CDT) has provided a new biocompatibility pathway for cancer therapy. Among them, Cu-based nanocatalysts with good biocompatibility and Fenton-like catalytic efficiency are considered to be a promising approach for enhancing CDT and CDT-involved multimodal synergies to improve the effectiveness of catalytic cancer therapy. Meanwhile, the emerging in situ therapy strategy promoted by Cu-based nanocatalysts has proven to exhibit attractive clinical application potential in replacing traditional chemotherapy and radiotherapy for cancer therapy with significant toxic side effects. In this work, the recent progress of various Cu-based nanocatalysts in cancer therapy was reviewed, especially the remarkable achievements in the catalytic treatment of cancer in the tumor microenvironment using CDT and CDT-involved multimodal synergies. In addition, the development expectations and challenges of Cu-based nanocatalysts in the field of cancer therapy were briefly summarized and discussed. We expect that this review will contribute to the development of Cu-based nanocatalysts for cancer therapy.

Immune checkpoint blockade (ICB) therapy has been approved for colorectal cancer (CRC). However, response rates are variable and often <50%. The low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) jointly contribute to this suboptimal response rate. This study confirmed the potential of combining immunogenic cell death (ICD) inducer irinotecan (IRI) and transforming growth factor-β (TGF-β) inhibitor galunisertib (GAL) to improve tumor immunogenicity and remodel the immunosuppressive TME. Moreover, to ameliorate the in vivo delivery barriers associated with small molecules, neutrophil micropharmacies (NOG) were developed for the codelivery of IRI and GAL, which loaded the commercial liposome formulation of IRI (ONIVYDE, ONI) intracellularly and conjugated the pH-responsive GAL liposome (GLP) on the cell surface. This neutrophil-based formulation resulted in a >4-fold increase in the ratios of the amount of both IRI and GAL accumulated in tumors to the dosage administration, effectively achieving multiple mechanism-mediated sensitization of CRC to ICB therapy.

Converting the "cold" tumor microenvironment (TME) to a "hot" milieu has become the prevailing approach for enhancing the response of immune-excluded/immunosuppressed colorectal cancer (CRC) patients to immune checkpoint blockade (ICB) therapy. During this process, inflammation accompanied by different kinds of chemokines/cytokines inevitably occurs. However, some activated inflammatory signals exhibit protumor potency. Therefore, strategies that preferentially activate antitumor inflammatory signaling rather than tumor-promoting signaling need to be developed. Herein, we constructed a STING agonist-loaded CuS/MnO 2 bimetallic nanosystem, termed diAMP-BCM. BCM with an optimized Cu/Mn ratio efficiently promoted the activation of proinflammatory signaling, and in combination with the STING agonist diAMP, diAMP-BCM controllably activated tumoricidal inflammatory signaling in APCs. DiAMP-BCM can efficiently generate ROS and promote the activation of STING, which induces the apoptosis of cancer cells and promotes the recruitment of monocytes while facilitating the polarization of macrophages and maturation of DCs. MC38 and CT26 CRC models were established to evaluate the in vivo antitumor effects of diAMP-BCM. Combined with ICB therapy, diAMP-BCM enables the rebuilding of tumor milieus with efficient tumor growth inhibition and alleviation of T-cell exhaustion, particularly in distal tumors, in sporadic colorectal cancer therapy. This study established a nanoplatform to promote the preferential activation of antitumor inflammatory signaling, rebuild the T-cell repertoire and alleviate T-cell exhaustion to enhance cancer ICB immunotherapy., Competing Interests: Declarations Ethics approval and consent to participate All animal procedures were performed following protocols approved by the Institutional Animal Care and Treatment Committee of Sichuan University (Chengdu, P. R. China) and West China Hospital, Sichuan University (Approved number: 2021755A) as well as Chengdu Medical College (Approved number: 2022037). Consent for publication Consents for publication were obtained from all the authors of this study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Hypoxia is one of the most typical features among various types of solid tumors, which creates an immunosuppressive tumor microenvironment (TME) and limits the efficacy of cancer treatment. Alleviating hypoxia becomes a key strategy to reshape hypoxic TME which improves cancer immunotherapy. However, it remains challenging to perform tumor precision therapy with controllable switches through hypoxia-activated gene editing and prodrugs to alleviate hypoxia. In this study, silica-coated second near-infrared window (NIR-II) emitting silver sulfide quantum dots are used as the carrier to load the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible factor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce the off-target effects in nontumor cells and better control safety risks, a TME-triggered cascade-activation nanodiagnostic and therapeutic platform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation of prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9 ribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic function of HIF-1α depletion by gene editing and TPZ activation. Importantly, targeting HIF-1α disrupts the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which effectively reshapes the immune-suppressive TME and activates T cell-mediated antitumor immunity. Taken together, we have provided a TME-triggered cascade-activation nanoplatform to alleviate hypoxia for improved cancer immunotherapy.

Disialoganglioside (GD2) is one of the most popular overexpressed antigens for tumor cell targeting. However, GD2-specific antibodies often show unintended targeting to GD2-expressing health-maintaining cells due to the comparable binding affinities both at physiological pH and in a slightly acidic tumor microenvironment (TME). In this work, an affinity-switchable zwitterionic PAMAM G5 dendrimer (G5-3S) is developed for selective binding to GD2 only in a slightly acidic TME. It has 3 sulfonic groups, 128 carboxylic groups, and 125 amino groups on the surface. This affinity switch is realized by multiple hydrogen bond (H-bond) formation between protonated carboxylic groups surrounding a sulfonic group and overexpressed GD2 clusters on the tumor cell membrane in the slightly acidic TME, whereas there is no stable H-bond formation at physiological pH. Thus, G5-3S shows superior selectivity to GD2-overexpressed tumor cells over anti-GD2 antibodies by avoiding targeting GD2-expressing health-maintaining cells at physiological pH. This suggests that G5-3S is a promising candidate for GD2-overexpressed cancer treatment.

Triple-negative breast cancer (TNBC) is highly heterogeneous, lacks accessible therapeutic targets, and features an immunosuppressive tumor microenvironment (TME). Anthracycline-based chemotherapy remains the primary treatment method for TNBC, while the current popular immune checkpoint inhibitors persistently encounter therapeutic resistance. Therefore, there is an urgent need to explore combined therapeutic strategies to remodel the TME and improve the treatment response. Considering the highly specific homing ability of tumor cell-derived vesicles and the key role of the signal transduction and activation of the transcription factor 3 (STAT3) pathway in TNBC, we propose a synergistic therapeutic strategy that integrates gene therapy, chemotherapy, and immunotherapy based on STAT3 short interfering RNA (siSTAT3) and doxorubicin (DOX)-functionalized tumor-derived extracellular vesicles (TEVs) (siSTAT3-DOX@TEV). The in vitro and in vivo results demonstrate that siSTAT3-DOX@TEV target tumor tissues precisely, downregulate STAT3 expression, and synergistically and efficiently induce immunogenic death, thereby reversing the immunosuppressive TME. Moreover, mass cytometry and immunohistochemistry reveal the local immune activation effect of siSTAT3-DOX@TEV, with a significant increase in M1 macrophages, CD4 + T cells, and CD8 + T cells in tumor tissues. These results provide strong hints for the development of TEV-based chemo-gene therapeutic agents for TNBC treatment at the clinical level.

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed. While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT. Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT 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 © 2024. Published by Elsevier Inc.)

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8 + tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67 + CD8 + T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641., Competing Interests: Declaration of interests D.D. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. D.D. also reports grants/research support (Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK.), consulting (ACM Bio, Ascendis, Castle, Clinical Care Options [CCO], Gerson Lehrman Group [GLG], Immunitas, Medical Learning Group [MLG], Replimmune, Trisalus, Xilio Therapeutics), speakers’ bureau (Castle Biosciences), steering committee membership (Immunocore, Replimmune) and patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work. P.D. is currently employed by Nanostring Technologies and reports stock options. Y.G.N. reports grants/research support (Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer) and consulting (Checkmate Pharmaceuticals) outside the submitted work. J.J.L. reports grants/research support (multiple), membership on data safety monitoring boards (multiple), membership on scientific advisory boards with no stock ownership or stock options (multiple), membership on scientific advisory boards with stock for (multiple), consulting (multiple) and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof) all outside the submitted work. D.M. is currently employed by Codiak Biosciences and reports stock options. D.B., J.W. and A.K. were formerly employed by CheckMate and report stock options. M.G.F. is currently employed by Regeneron Pharmaceuticals Inc. and reports stock options. J.M.K. reports grants/research support (Bristol-Myers Squibb, Amgen Inc.) and consulting (Bristol-Myers Squibb, Checkmate Pharmaceuticals, Novartis, Amgen Inc., Checkmate, Castle Biosciences, Inc., Immunocore LLC, Iovance, Novartis.) outside the submitted work. J.M.T. reports grants and consulting from Bristol-Myers Squibb, Merck Sharp & Dohme, Astra Zeneca, and Compugen outside the submitted work. H.M.Z. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. H.M.Z. also reports grants/research support (NIH/NCI, Bristol-Myers Squibb and GlaxoSmithKline), personal fees (GlaxoSmithKline, Bayer, and Vedanta) and pending provisional patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung cancer brain metastasis (LCBM) poses a significant clinical challenge due to acquired resistance to tyrosine kinase inhibitor (TKI) treatment. To elucidate its underlying mechanisms, we employed single-cell RNA sequencing analysis on surgically obtained LCBM samples with diverse genetic backgrounds and TKI treatment histories. Our study uncovers that TKI treatment elevates the immune checkpoint CTLA4 expression in T cells, promoting an immune-suppressive microenvironment. This immunomodulation is initiated by tumor-derived HMGB1 in response to TKIs. In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant EGFR mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As a novel noninvasive tumor therapy, sonodynamic therapy (SDT) attracts booming concerns. However, the limited water solubility, inadequate biocompatibility, and low targeting ability of conventional sonosensitizers significantly hinder their potential for clinical application. Herein, novel zinc(II)-porphyrin nanotheranostics (HA@Zn-TCPP) were fabricated in which the zinc(II)-porphyrin (TCPP) metal-organic framework was first constructed by a simple thermal reaction, followed by the addition of hyaluronic acid (HA) for modification. The specific targeting ability of HA facilitated the internalization of HA@Zn-TCPP within tumor cells, resulting in its preferential accumulation in tumor tissues that exhibit CD44 receptor overexpression. The acidic tumor microenvironment induced the rapid decomposition of HA@Zn-TCPP, releasing free TCPP for activating SDT. This controllable generation of reactive oxygen species (ROS) could effectively decrease damage to normal tissues. The HA@Zn-TCPP exhibited remarkable antitumor effects in experiments, achieving a tumor inhibition rate of up to 82.1% when under ultrasound. This finding provides an imperative strategy to develop novel sonosensitizers for enhanced SDT.

Photodynamic therapy (PDT), owing to its low invasiveness, high efficiency, fewer side effects, spatiotemporal controllability and good selectivity, has attracted increasing attention for its tremendous potential in revolutionizing conventional strategies of tumor treatment. However, hypoxia is a common feature of most malignancies and has become the Achilles' heel of PDT. Currently, Type II photosensitizers (PSs) have inadequate efficacy for PDT due to the inherent oxygen consumption of the anoxic tumor microenvironment. Moreover, due to the absence of a general molecular design strategy and the limitations imposed by the energy gap law, Type-I PSs are less reported. Therefore, the development of Type-I PSs with hypoxia resistant capabilities is urgently required. Herein, in this study, we have obtained pure Type-I materials for the first time by employing a strategy that decreases the triplet energy levels of the π-conjunction bridge. A sufficient donor-acceptor interaction reduces the lowest triplet energy level and aids in the transfer of excitons from singlet to triplet levels. With this strategy, dibenzofulvene derivatives (FEs) displayed purely Type-I ROS generation. Among them, FE-TMI exhibits superior Type-I reactive oxygen species-generation performance, showcasing the great potential of PDT in treating tumor cells under hypoxic conditions and several types of solid tumors in mouse in vivo experiments. This work provides a practical solution for the future design of Type-I PDT materials and is aimed at enhancing PDT efficiency.

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Cancer immunotherapy is often hindered by an immunosuppressive tumor microenvironment (TME). Various strategies are being evaluated to shift the TME from an immunologically 'cold' to 'hot' tumor and hereby improve current immune checkpoint blockades (ICB). One particular hot topic is the use of combination therapies. Here, we set out to screen a variety of metallic nanoparticles and explored their in vitro toxicity against a series of tumor and non-tumor cell lines. For silver nanoparticles, we also explored the effects of core size and surface chemistry on cytotoxicity. Ag-citrate-5 nm nanoparticles were found to induce high cytotoxicity in Renca cells through excessive generation of reactive oxygen species (ROS) and significantly increased cytokine production. The induced toxicity resulted in a shift of the immunogenic cell death (ICD) marker calreticulin to the cell surface in vitro and in vivo. Subcutaneous Renca tumors were treated with anti-PD1 or in combination with Ag-citrate-5 nm. The combination group resulted in significant reduction in tumor size, increased necrosis, and immune cell infiltration at the tumor site. Inhibition of cytotoxic CD8 + T cells confirmed the involvement of these cells in the observed therapeutic effects. Our results suggest that Ag-citrate-5 nm is able to promote immune cell influx and increase tumor responsiveness to ICB therapies., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs' activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer's development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs' involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies., (© 2024. The Author(s).)

PANoptosis has recently emerged as a potential approach to improve the immune microenvironment. However, current methods for inducing PANoptosis are limited. Herein, through biological screening, the rational use of the nutrient metal ions Cu 2+ and Zn 2+ had great potential to induce PANoptosis. Inspired by these findings, we successfully developed hydrazided hyaluronic acid-modified zinc copper oxide (HZCO) nanoparticles as a PANoptosis inducer to potentiate immunotherapy. Bioactive HZCO actively delivered Cu 2+ and Zn 2+ while disrupting the cellular intrinsic ion metabolism pathway, resulting in double-stranded DNA release and organelle damage in cancer cells. Simultaneously, this process triggered the formation of PANoptosome and the activation of PANoptosis. HZCO-induced PANoptosis inhibited tumor growth and activated potent antitumor immune response, thereby enhancing the effectiveness of anti-programmed cell death 1 therapy. Overall, our work provides an insight into the development of PANoptosis inducers and the design of synergistic immunotherapy strategies.

The tumor microenvironment (TME) is characterized by low pH, hypoxia, and overexpression of glutathione (GSH). Owing to the complexity of tumor pathogenesis and the heterogeneity of the TME, achieving satisfactory efficacy with a single treatment method is difficult, which significantly impedes tumor treatment. In this study, composite nanoparticles of calcium-copper/alginate-hyaluronic acid (HA) (CaO 2 -CuO 2 @SA/HA NC) with pH and GSH responsiveness were prepared for the first time through a one-step synthesis using HA as a targeting ligand. Nanoparticles loaded with H 2 O 2 can enhance the chemodynamic therapy effects. Simultaneously, Cu 2+ can generate oxygen in the TME and alleviate hypoxia in tumor tissue. Cu 2+ and H 2 O 2 undergo the Fenton reaction to produce cytotoxic hydroxyl radicals and Ca 2+ ions, which enhance the localization and clearance of nanoparticles in tumor cells. Additionally, HA and sodium alginate (SA) were utilized to improve the targeting and biocompatibility of the nanoparticles. Fourier transform infrared, x-ray diffraction, dynamic light scattering, SEM, transmission electron microscope, and other analytical methods were used to investigate their physical and chemical properties. The results indicate that the CaO 2 -CuO 2 @SA/HA NC prepared using a one-step method had a particle size of 220 nm, a narrow particle size distribution, and a uniform morphology. The hydrogen peroxide self-supplied nanodrug delivery system exhibited excellent pH-responsive release performance and glutathione-responsive •OH release ability while also reducing the level of reactive oxide species quenching. In vitro cell experiments, no obvious side effects on normal tissues were observed; however, the inhibition rate of malignant tumors HepG2 and DU145 exceeded 50%. The preparation of CaO 2 -CuO 2 @SA/HA NC nanoparticles, which can achieve both chemokinetic therapy and ion interference therapy, has demonstrated significant potential for clinical applications in cancer therapy., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Purpose: The poor delivery and limited penetration of nanoparticles into breast cancer tumors remain essential challenges for effective anticancer therapy. This study aimed to design a promising nanoplatform with efficient tumor targeting and penetration capability for effective breast cancer therapy., Methods: A pH-sensitive mitoxantrone (MTO) and copper ion-loaded nanosystem functionalized with cyclic CRGDfK and r9 peptide (TPRN-CM) was rationally designed for chemo-chemodynamic combination therapy. TPRN-CM would be quiescent in blood circulation with the CRGDfK peptide on the surface of the nanoparticle to improve its targeting to the tumor. Then, the structure of TPRN-CM changes in the acidic tumor microenvironment, and the r9 peptide can be exposed to make a surface charge reversal to promote deep penetration in the tumor and facilitate their internalization by cancer cells, which was characterized using transmission electron microscopy, dynamic light scattering, flame atomic absorption, etc. The drug release behavior, anti-tumor effects in vivo and in vitro, and the biosafety of the nanoplatform were evaluated., Results: TPRN-CM exhibited remarkable capability to load MTO and Cu 2+ with good stability in serum. It can achieve pH-responsive charge reversal, MTO, and Cu 2+ release, and can further generate toxic hydroxyl radicals in the presence of glutathione (GSH) and H 2 O 2 . In vitro experiments demonstrated that this nanoplatform significantly inhibited proliferation, migration, invasion activities and 3D-tumorsphere growth. In vivo experiments suggested that rationally designed TPRN-CM can be effectively delivered to breast cancer tumors with deep tumor penetration, thereby resulting in a notable reduction in tumor growth and suppression of lung metastasis without causing any apparent side effects., Conclusion: The constructed TPRN-CM nanoplatform integrated tumor targeting, tumor penetration, drug-responsive release, and chemo-chemodynamic combination therapy, thereby providing an intelligent drug delivery strategy to improve the efficacy of breast cancer treatment., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Tan et al.)