bims-flamet 2025-11-02 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–11–02
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI

Bacteria modulate tumor-associated macrophages to combat cancer.
[The Role of Tumor‒Draining Lymph Nodes in Photoimmunotherapy Targeting Cancer‒Associated Fibroblasts].
Cannabidivarin directly targets the immunosuppressive activity of regulatory myeloid cells in tumors.
Roles of tumor-associated macrophages in triple-negative breast cancer progression.
Cancer-derived exosomes: mediators of immune crosstalk and emerging targets for immunotherapy.
Communication between gut microbiota-derived metabolites and the tumor microenvironment.
The mechanism and research progress of PD-1/PD-L1 on immune escape of lung cancer.
Co-treatment of ticagrelor and anti-PD-1 immunotherapy in tumor-associated macrophages reduces pancreatic cancer cell growth and migration through the TGF-β1/Smad2 pathway.
Lactate and lactylation in cancer: drivers of immune suppression and microenvironmental reprogramming.
IFNγ-mediated suppression of alternative NF-κB in tumor-resident myeloid cells promotes selective recruitment of cytotoxic but not regulatory T cells.
Gamma-delta T cells in breast cancer: Dual role in tumor immunity and emerging therapeutic approaches.
Microenvironmental regulation and remodeling of breast cancer angiogenesis: from basic mechanisms to clinical therapeutic implications.
MSC-delivered CXCL10 for solid tumors: Navigating the translational hurdles from precept to clinic.
Cross-talk between cancer and diabetes: Exploring shared molecular pathways in cellular metabolism and signaling.
Role of cytokine-based immunotherapy approaches in gastrointestinal cancers.
Myeloid-derived suppressor cells inhibit the replication of oncolytic virus by reducing intratumoral arginine levels.
Research Advances in Cancer-Associated Fibroblasts in Prostate Cancer Progression.
Editorial: Interplay of immunity and ECM in cancer.
Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
HypoxamiRs in pancreatic cancer: master regulators of the hypoxic tumor microenvironment.
Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.

Crit Rev Oncol Hematol. 2025 Oct 23. pii: S1040-8428(25)00371-3. [Epub ahead of print]216 104983

Bacteria modulate tumor-associated macrophages to combat cancer.

Zonghai Chen, Jingxuan Li, Jingjing Wang, Yufei Bai, Zhang Zhang, Guofu Chen, Xuan Cao, Dexi Jin.

  Tumor microenvironment (TME) is a manipulator of tumorigenesis and development, which consists of tumor cells, immune cells, fibroblasts, intercellular stroma, microvasculature, and a variety of biomolecules. Bacteria and tumor-associated macrophages (TAMs) are essential elements of the TME. TAMs and bacteria can be altered and recruited by tumor cells, and the interaction between controlled bacteria and TAMs accelerates tumor progression. Reshaping the TME by regulating macrophages through intratumoral bacteria may be a new anti-tumor strategy. However, the mechanisms underlying bacterial-macrophage interactions and how bacteria regulate macrophages to combat tumors remain poorly understood. This review summarizes the relationships among bacteria, macrophages, and tumors within the tumor microenvironment, as well as recent advances in bacteria-targeted regulation of macrophage antitumor activity.

Keywords:  Anti-tumor; Bacteria; Tumor; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104983
Gan To Kagaku Ryoho. 2025 Oct;52(10): 743-745

[The Role of Tumor‒Draining Lymph Nodes in Photoimmunotherapy Targeting Cancer‒Associated Fibroblasts].

Tatsuya Takahashi, Kazuhiro Noma, Akihito Shimizu, Tasuku Matsumoto, Seitaro Nishimura, Yasushige Takeda, Hijiri Matsumoto, Tomoyoshi Kunitomo, Hajime Kashima, Satoru Kikuchi, Toshiaki Ohara, Shunsuke Tanabe, Hiroshi Tazawa, Toshiyoshi Fujiwara.

To effectively induce anti‒tumor immune responses, it is essential that tumor‒specific T cells are generated within the tumor microenvironment (TME), a process in which tumor‒draining lymph nodes (TDLNs) are thought to play a critical role. We have previously demonstrated that photoimmunotherapy targeting cancer‒associated fibroblasts (PIT‒CAF), which specifically targets the fibroblast activation protein (FAP), modulates the immune cell composition and function within the TME. In this study, we investigated the effects of CAFs and PIT‒CAF on tumor‒specific T cells in both the TME and TDLNs.
Biomed Pharmacother. 2025 Oct 27. pii: S0753-3322(25)00891-1. [Epub ahead of print]192 118697

Cannabidivarin directly targets the immunosuppressive activity of regulatory myeloid cells in tumors.

Miryam Steinberg, Iris Wyrobnik, Shiri Procaccia, Ronen Rosenblum, Anat Gelfand, Shaked Avisidris, Hila Novak-Kotzer, David Meiri.

  Immunosuppression within the tumor microenvironment (TME) is a major obstacle for effective cancer immunotherapy. This is largely driven by myeloid suppressor cells, specifically Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs), which create an environment that inhibits the immune response. The presence of these cells is strongly correlated with poor patient outcomes and resistance to treatment, highlighting the need for new strategies to mitigate their effects. In this study, we investigated the therapeutic potential of Cannabidivarin (CBDV), a less-studied non-psychoactive cannabinoid, to reprogram these immunosuppressive cells. We found that CBDV directly targets myeloid suppressor cells, significantly impairing their immunosuppressive function both in vitro and in vivo. Mechanistically, CBDV reduces the key immunosuppressive markers inducible, Nitric Oxide Synthase (iNOS) and Arginase-1 (Arg-1) in murine MDSCs and promotes the differentiation of TAMs into M1-like macrophages. This shift in myeloid cell function leads to restored CD8 + T-cell proliferation and activation. Furthermore, our results show that CBDV treatment in tumor-bearing mice reduces tumor progression and improves the anti-tumor immune response within the TME. We also confirmed the clinical relevance of our findings, demonstrating that CBDV effectively reduces the immunosuppressive phenotype of human-derived myeloid cells. Altogether, these results establish CBDV as a new immunotherapeutic agent that directly neutralizes myeloid suppressor cells, thereby enhancing the immune system's response against cancer.

Keywords:  Arg-1; CBDV; Cancer; Cannabis; Immunotherapy; MDSC; TAM; Tumor microenvironment; iNOS

DOI:  https://doi.org/10.1016/j.biopha.2025.118697
Front Immunol. 2025 ;16 1677363

Roles of tumor-associated macrophages in triple-negative breast cancer progression.

Tianhai Wu, Yuling Liao.

  Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It is associated with a high risk of recurrence, metastasis, and limited therapeutic options. Tumor-associated macrophages (TAMs) play a central role in TNBC progression by shaping an immunosuppressive tumor microenvironment. Primarily polarized toward an M2-like phenotype under the influence of cytokines such as IL-10 and TGF-β, TAMs facilitate tumor growth, angiogenesis, metastasis, and immune evasion through multiple mechanisms. This review summarizes current understanding of TAM recruitment, polarization, and pro-tumoral functions in TNBC, and outlines emerging therapeutic strategies aimed at depleting TAMs, reprogramming them to an anti-tumor M1-like state, or blocking the CD47-SIRPα phagocytosis checkpoint. These approaches offer promising avenues for reprogramming the TNBC microenvironment and improving clinical outcomes.

Keywords:  TAM; immune evasion; triple-negative breast cancer; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1677363
Front Immunol. 2025 ;16 1679934

Cancer-derived exosomes: mediators of immune crosstalk and emerging targets for immunotherapy.

Ridwan Mahamed, Bernice Monchusi, Clement Penny, Sheefa Mirza.

  Exosomes, nanoscale extracellular vesicles secreted by various cell types, play pivotal roles in intercellular communication. In cancer, tumor-derived exosomes-referred to as cancer-derived exosomes (CDEs)-have emerged as critical regulators of immune evasion, tumor progression, and therapy resistance within the tumor microenvironment (TME). CDEs modulate immune cell function through the transfer of immunosuppressive proteins, cytokines, and non-coding RNAs, ultimately reprogramming immune surveillance mechanisms. This review provides an in-depth analysis of how CDEs influence major immune cell subsets-including T cells, B cells, NK cells, dendritic cells, macrophages, and myeloid-derived suppressor cells-thereby establishing an immunosuppressive TME. We also explore the potential of immune cell-derived exosomes (IDEs) as emerging immunotherapeutic tools capable of counteracting the suppressive effects of CDEs. Furthermore, we highlight exosome engineering strategies aimed at improving therapeutic cargo delivery, tumor targeting, and antitumor immune activation. Finally, we discuss how exosome profiling offers promise in liquid biopsy diagnostics and how integration with 3D tumor models and advanced bioengineering can accelerate the clinical translation of exosome-based cancer immunotherapies.

Keywords:  cancer-derived exosomes; immune-crosstalk; immune-modulation; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1679934
Front Immunol. 2025 ;16 1649438

Communication between gut microbiota-derived metabolites and the tumor microenvironment.

Xinyi Hu, Bo Li, Yuanqing Li, Yushan Liang, Tingting Huang.

  The gut microbiota has been increasingly recognized as a critical player in maintaining human health and influencing disease development. The tumor microenvironment (TME) is pivotal in tumor development and progression, comprising immune cells, stromal elements, extracellular matrix components, and cytokines. Recent studies have highlighted the promising potential of gut microbiota-derived metabolites (e.g., short-chain fatty acids, bile acids, polyamines, and tryptophan derivatives) to reshape the TME in various ways, generating significant interest for the development of novel therapeutic strategies. Beyond their established effects on traditional cancer treatments, emerging evidence suggests that microbiome-based interventions can substantially enhance cancer immunotherapy. However, the variable role of gut microbiota in modulating therapeutic responses complicates the prediction of clinical outcomes. Therefore, understanding the crosstalk between the gut microbiota and the TME is crucial and holds promise for the development of personalized and comprehensive cancer management strategies. This review aims to summarize the reciprocal regulatory mechanisms between gut microbiota-derived metabolites and the TME, and to explore how these interactions can be leveraged to improve cancer immunotherapy.

Keywords:  cancer immunotherapy; crosstalk; gut microbiota; gut microbiota-derived metabolites; immune cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1649438
Transl Cancer Res. 2025 Sep 30. 14(9): 6041-6051

The mechanism and research progress of PD-1/PD-L1 on immune escape of lung cancer.

Zhenyu Li, Tan Wang, Jimin Liu, Wenlong Qi, Qingguo Lv, Yannan Xu, Lin Tian.

  According to the latest Global Cancer Observatory (GLOBOCAN) 2022 estimates, lung cancer remains the second most commonly diagnosed cancer worldwide, with approximately 2.48 million new cases (11.4% of all cancer diagnoses) and over 1.86 million deaths (18.2% of all cancer-related deaths), making it the leading cause of cancer mortality globally. It has been reported that programmed death ligand 1 (PD-L1) is confirmed to interact with the tumor microenvironment (TME) to mediate the immune escape of lung cancer. PD-L1, which is highly expressed in lung cancer cells, activates the programmed death receptor 1 (PD-1)/PD-L1 signaling pathway by binding to PD-1, thereby inhibiting the function of lymphocytes and the release of cytokines, inducing activated lymphocyte apoptosis, resisting the killing effect of lymphocytes, ultimately leading to immune escape in lung cancer. PD-L1 inhibitors, a hot spot in tumor immunotherapy, can restore the activity of T cells, thereby enhancing the body's immune response, and ultimately enabling the immune system to effectively recognize and kill lung cancer cells, thereby enabling lung cancer patients to achieve long-term tumor remission. At present, a variety of PD-L1 inhibitors have been approved for application and have achieved good clinical efficacy in the treatment of lung cancer. This article reviews the research progress of the interaction between PD-L1 and the TME to mediate immune escape from lung cancer and the role of PD-L1 inhibitors in the treatment of lung cancer.

Keywords:  Lung cancers; immune evasion; immune responses; mechanism; research progress

DOI:  https://doi.org/10.21037/tcr-2025-230
Biomed Pharmacother. 2025 Oct 28. pii: S0753-3322(25)00889-3. [Epub ahead of print]192 118695

Co-treatment of ticagrelor and anti-PD-1 immunotherapy in tumor-associated macrophages reduces pancreatic cancer cell growth and migration through the TGF-β1/Smad2 pathway.

Ying Kang, Emmanuel Boadi Amoafo, Philomena Entsie, Buddhadev Layek, Paul M Grandgenett, Michael A Hollingsworth, Marina Pasca di Magliano, Elisabetta Liverani.

  Pancreatic ductal adenocarcinoma (PDAC) is the third primary cause of cancer-related mortality in the US. PDAC is associated with an immunosuppressive tumor microenvironment (TME) that restricts the effectiveness of immunotherapies. Immunosuppressive tumor-associated macrophages (TAMs), the most abundant cell type in TME, express immune checkpoint ligands, including programmed cell death protein 1 (PD-1) ligand 1 (PD-L1). Targeting PD-1/PD-L1 alone has no effect in PDAC, highlighting the need for combination approaches. P2Y12, an ADP receptor, is expressed by macrophages, and P2Y12 antagonists promote phagocytosis, in turn, is linked to anti-tumor activity. Here, we tested the combined blockade of PD-1/PD-L1 and P2Y12 on TAMs in pancreatic cancer. For this purpose, we set up co-cultures of pancreatic cancer cells and TAMs and treated them with inhibitor BMS-1, which blocks PD-1/PD-L1 interaction, cemiplimab to block PD-1, and ticagrelor to block P2Y12. We observed that the co-treatment of ticagrelor and cemiplimab promoted TAM phagocytic ability and inhibited the TAM-induced growth and migration of cancer cells. The combination of ticagrelor and cemiplimab inhibited TGF-β1 release from TAMs and Smad2 phosphorylation in cancer cells. Our data suggest that co-treatment of ticagrelor and cemiplimab in TAMs inhibits pancreatic cancer cell growth and migration by suppressing the TGF-β1/Smad2 signaling pathway, providing an emerging strategy aimed at re-educating or depleting TAMs to enhance the efficacy of immunotherapy in pancreatic cancer.

Keywords:  P2Y(12); PD-1; PD-L1; PDAC; TME; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.biopha.2025.118695
Exp Hematol Oncol. 2025 Oct 28. 14(1): 128

Lactate and lactylation in cancer: drivers of immune suppression and microenvironmental reprogramming.

Xiaoyu Ji, Limin Xia.

  Lactate, a key metabolite of the Warburg effect, plays a central role in shaping multiple hallmarks of cancer. Through lactate shuttling and engagement with specific receptors, it activates downstream signaling pathways that remodel the tumor microenvironment (TME) and facilitate tumor progression. More recently, lysine lactylation-an emerging post-translational modification derived from lactate-has been identified as a crucial epigenetic mechanism that links altered tumor metabolism with transcriptional regulation. Lactylation has been implicated in promoting tumor proliferation, metastasis, stemness maintenance, immune evasion, and therapeutic resistance across various cancer types. Both tumor and immune cells undergo lactylation, which modulates gene expression and contributes to the immunosuppressive landscape of the TME. Targeting lactate production and transport has shown promise in suppressing tumor growth and enhancing immunotherapeutic efficacy. In this review, we comprehensively discuss the functional roles and underlying mechanisms of lactate and lactylation in cancer progression, with a particular focus on their impact within the TME. We also highlight recent advances in targeting these metabolic processes as potential therapeutic strategies, aiming to provide new perspectives for improving cancer treatment outcomes.

Keywords:  Lactate; Lactylation; Targeting therapy; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1186/s40164-025-00719-3
Front Immunol. 2025 ;16 1681777

IFNγ-mediated suppression of alternative NF-κB in tumor-resident myeloid cells promotes selective recruitment of cytotoxic but not regulatory T cells.

Adam Brinkman, Ravikumar Muthuswamy, Bowen Dong, Robert P Edwards, Pawel Kalinski.

  Immunotherapy is currently effective in less than half of patients with solid tumors, and most responders develop secondary progression. High infiltration of the tumor microenvironment (TME) with CD8+ cytotoxic T cells (CTLs) and low infiltration with regulatory T cells (Treg) predicts the patients' responses to immunotherapy and long-term outcomes. To identify the mechanisms regulating long-term stability of CTL infiltration, we analyzed the impact of CTL-produced cytokines on the TME by co-culturing patient-isolated ascites cells with activated T cells. Unexpectedly, we observed that activated CTLs selectively induce cytotoxic T cell-attracting chemokines but not chemokines that attract T regulatory cells in ovarian cancer TME and tumor-associated myeloid cells, resulting in recruitment of additional CTLs without Tregs. This selectivity resulted from the unique dependence of CCL22 induction on both canonical and alternative NF-κB and the suppression of alternative NF-κB signaling by T cell-released IFNγ. Our data demonstrate that T cell-produced IFNγ suppresses alternative NF-κB signaling in TME-associated myeloid cells, allowing for the induction of CTL-attracting chemokines with the concomitant suppression of Treg-attracting CCL22. These novel functions of IFNγ and activated T cells in regulating the balance between canonical and alternative NF-κB signaling in myeloid cells provide new opportunities to enhance and stabilize the selective CTL influx in the TME.

Keywords:  CTLs; Tregs (regulatory T cells); alternative NF-κB; chemokines; interferon gamma (IFNγ); myeloid cells; tumor micro environment (TME)

DOI:  https://doi.org/10.3389/fimmu.2025.1681777
Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(25)00119-4. [Epub ahead of print]398 185-207

Gamma-delta T cells in breast cancer: Dual role in tumor immunity and emerging therapeutic approaches.

Silvia Silva-Romeiro, María Luisa Sánchez-León, Carlos Jiménez-Cortegana, Rubén de Toro-Salas, Jesús Machuca Aguado, Víctor Sánchez-Margalet, Luis de la Cruz-Merino.

  Gamma delta (γδ) T cells are a unique subset of T lymphocytes capable of bridging innate and adaptive immunity. Unlike αβ T lymphocytes, γδ T cells bypass the need for Major Histocompatibility Complex (MHC)-restricted antigen presentation, allowing them to rapidly respond to stress signals in contexts such as infections and cancer. In breast cancer (BC), γδ T cells play a dual role, exhibiting both anti-tumoral and pro-tumoral activities. Their capacity for direct cytotoxicity, cytokine production, and antigen presentation highlights their versatility within the tumor microenvironment (TME). The prognostic impact of γδ T cells in BC is complex and varies depending on their density, subset, and functional state. While Vδ1 + γδ T cells have been associated with improved survival, particularly in triple-negative BC, other subsets, such as IL-17-producing γδ T cells, contribute to tumor progression, promoting angiogenesis and immune suppression. The emerging therapeutic potential of γδ T cells resides in their MHC-independent activity and stress antigen recognition, highlighting their potential value in cancer immunotherapy, including adoptive cell therapies (e.g., chimeric antigen receptor-T approaches). Additionally, the combination of γδ T cells with immune checkpoint inhibitors or tumor-targeting antibodies has shown promise in overcoming the immunosuppressive challenges of the TME.

Keywords:  Breast cancer; Gamma delta T cells; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.013
Discov Oncol. 2025 Oct 27. 16(1): 1973

Microenvironmental regulation and remodeling of breast cancer angiogenesis: from basic mechanisms to clinical therapeutic implications.

Ziling Zhou, Hanyi Zhong, Han Wang, Shoutang Wang, Wala Ben Kridis, Ruo Wang, Kunwei Shen, Zheng Wang, Renhong Huang.

  Angiogenesis, the formation of new blood vessels, is a pivotal process in breast cancer (BC) progression and metastasis, intricately regulated by complex interactions within the tumor microenvironment (TME). While the vascular endothelial growth factor (VEGF) pathway represents a cornerstone of these pro-angiogenic mechanisms, resistance to anti-VEGF therapies is common, underscoring the involvement of alternative pathways. Key insights reveal that hypoxia, metabolic reprogramming, and stromal components including cancer-associated fibroblasts (CAFs), cancer-associated adipocytes (CAAs) and immune cells, cooperate to drive aberrant angiogenesis and treatment resistance. This review synthesizes emerging evidence on the multifaceted regulation of angiogenesis by endothelial cells (ECs), pericytes, immune cells, and stromal components in shaping the angiogenic landscape, and discusses innovative therapeutic strategies. These include hypoxia-targeted agents, immune modulation, and combination therapies that co-target compensatory pathways. We emphasize that overcoming resistance requires integrated approaches that remodel the TME rather than solely inhibiting VEGF. Finally, we highlight ongoing clinical trials and translational opportunities aimed at improving outcomes and reducing metastasis in breast cancer patients.

Keywords:  Angiogenesis; Breast cancer; Immune cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-03797-1
Biomed Pharmacother. 2025 Oct 30. pii: S0753-3322(25)00929-1. [Epub ahead of print]193 118735

MSC-delivered CXCL10 for solid tumors: Navigating the translational hurdles from precept to clinic.

Dujiang Yang, Guoyou Wang.

The recent study by Yoon et al. (Biomed Pharmacother. 2025) presents an innovative strategy to augment adoptive T cell therapy (ACT) for solid tumors by employing mesenchymal stromal cells (MSCs) engineered for tumor-targeted delivery of CXCL10. While the preclinical data compellingly demonstrate enhanced T-cell infiltration and antitumor efficacy, a substantive critique reveals profound challenges that threaten its clinical translation. The foundational premise of using MSCs as a delivery vehicle is critically undermined by their well-documented functional plasticity; within the tumor microenvironment (TME), these cells risk adopting pro-tumorigenic phenotypes, including differentiation into cancer-associated fibroblasts that promote desmoplasia or secretion of factors like VEGF that drive angiogenesis. Concurrently, the pleiotropic nature of CXCL10 signaling represents a significant biological paradox. While intended to recruit cytotoxic T-cells, this chemokine axis is also a potent recruiter of CXCR3 + immunosuppressive populations, notably regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby potentially fostering an immune-suppressive niche that could counteract therapeutically recruited effectors. Furthermore, the translational pathway is fraught with additional hurdles: the limited fidelity of immunocompetent murine models to human TME heterogeneity, significant scalability and batch-to-batch variability issues in manufacturing clinical-grade engineered MSCs, and unresolved safety concerns pertaining to lentiviral-mediated transgenesis. Therefore, while conceptually elegant, the clinical viability of this platform is contingent upon future studies providing rigorous in vivo fate-mapping of administered MSCs, comprehensive immune profiling to delineate the net immunomodulatory outcome, and the development of robust combinatorial strategies, such as coupling with immune checkpoint blockade, to mitigate these inherent risks. Addressing these core issues is paramount to advancing this potent preclinical proof-of-concept into a safe and effective therapeutic modality.

DOI: https://doi.org/10.1016/j.biopha.2025.118735
Mol Aspects Med. 2025 Oct 27. pii: S0098-2997(25)00084-6. [Epub ahead of print]106 101420

Cross-talk between cancer and diabetes: Exploring shared molecular pathways in cellular metabolism and signaling.

Zhangzhi Tang, Nuo Xu, Pin Lyu, Hui Zhao, Wenjie Zheng.

  Diabetes and cancer are among the most prevalent chronic diseases globally, drawing increasing attention due to their shared features of metabolic and signaling dysregulation. Epidemiological evidence indicates that type 2 diabetes significantly elevates the risk of developing multiple types of tumors. This review highlights the key molecular intersections between diabetic pathophysiology and oncogenic processes, with a focus on how hyperinsulinemia and hyperglycemia contribute to tumor initiation and progression. These effects are primarily mediated through profound metabolic reprogramming, including hyperactivation of the hexosamine biosynthetic pathway (HBP) and the accumulation of advanced glycation end-products (AGEs), which promote sustained oxidative stress and chronic inflammation. Consequently, the tumor microenvironment (TME) undergoes substantial remodeling. The metabolism and function of immune cells are disrupted, promoting immune evasion. Meanwhile, cancer cells adapt by engaging mechanisms such as diabetes-induced epigenetic reprogramming, activation of the unfolded protein response (UPR), and alterations in the gut microbiota, thereby enhancing their survival advantage. Emerging evidence suggests that anti-diabetic agents targeting these metabolic intersections exhibit dual roles in cancer therapy, offering both therapeutic potential and potential risks. To address these complexities, future efforts should conduct multi-omics technologies to dissect the metabolic heterogeneity of diabetes-associated tumors, paving the way for precise and personalized therapeutic strategies for patients with this comorbidity.

Keywords:  Cancer; Diabetes; Epigenetic reprogramming; Immune microenvironment; Metabolic reprogramming; Signaling pathway; Therapy

DOI:  https://doi.org/10.1016/j.mam.2025.101420
Cytokine Growth Factor Rev. 2025 Oct 23. pii: S1359-6101(25)00140-6. [Epub ahead of print]86 149-166

Role of cytokine-based immunotherapy approaches in gastrointestinal cancers.

Rafik ElBeblawy, Midhun Malla, Mehmet Akce.

  Gastrointestinal (GI) cancers are among the most common leading causes of cancer-related mortality globally and they are the leading cause of cancer-related mortality in the US. Immune checkpoint inhibitor (ICI)-based therapies altered treatment paradigm in several tumor types including GI cancers. Despite encouraging results in select GI cancers, response rate is low, and treatment resistance poses a challenge in clinical practice. Cytokines are soluble mediators that regulate immune responses and can either promote or inhibit tumor growth depending on their impact on the tumor microenvironment (TME). In GI cancers, chronic inflammation driven by cytokines such as IL-6, IL-10, TNF-α, and TGF-β facilitates immune evasion and tumor progression. Cytokines contribute to the histopathogenesis of GI cancers by driving chronic inflammation, promoting epithelial-to-mesenchymal transition, and remodeling the TME to favor immunosuppression and angiogenesis. This cytokine-mediated landscape not only supports tumor initiation and progression but also influences systemic therapy outcomes by fostering resistance to chemotherapy and dampening responsiveness to immunotherapy. Integrating cytokine-targeted strategies with ICIs may enhance antitumor immunity by reversing T-cell exhaustion, improving effector T cell infiltration and function, and reprogramming the tumor milieu toward a pro-inflammatory, immune-permissive state potentially overcoming resistance and improving clinical efficacy. While ICIs have attracted most of the research interest in the past decade, cytokine-based therapy is another frontier to be utilized as either a therapeutic agent or a target to regulate cancer immunogenicity. In this review we aim to present a comprehensive discussion about relevant cytokines in GI cancers and explain mechanism of cytokines in immune regulation, discuss therapeutic potential of different cytokines, interleukins, interferons, tumor growth factors and their clinical application in recent clinical trials either alone or combined with other immunotherapeutic agents in GI cancers. Additionally, we discuss the potential limitations and challenges of cytokine-based immunotherapy in GI cancers.

Keywords:  Cytokines; Gastrointestinal cancers; Growth factors; Immunotherapy; Interleukins; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2025.10.005
Mol Ther Oncol. 2025 Dec 18. 33(4): 201066

Myeloid-derived suppressor cells inhibit the replication of oncolytic virus by reducing intratumoral arginine levels.

Parker Dryja, Erica B Flores, Mee Y Bartee, Viswanathan Palanisamy, Eric Bartee.

  Oncolytic virotherapy uses replication-competent viruses to treat various solid tumors. While much of the clinical efficacy of oncolytic virotherapy is mediated by anti-tumor T cell responses, most of these therapies still rely on the in vivo replication of the viral agents within infected tumor cells. Understanding the fundamental mechanisms that govern this replication therefore remains essential to the clinical application of these therapies. As viruses, oncolytic agents rely entirely on host metabolites and resources for their propagation. To address this gap in knowledge, we asked which cells impacted the intratumoral replication of oncolytic myxoma virus during treatment of B16F10 melanomas. Our results demonstrate that myxoma replication is potently restricted by the presence of intratumoral arginase-1+ myeloid-derived suppressor cells, which prevent the spread of oncolytic infection by catabolizing intratumoral arginine supplies. Additionally, either pharmacological depletion of these cells or genetic ablation of their arginase-1 expression markedly improves intratumoral myxoma infection and enhances the therapeutic efficacy of viruses. Collectively, these results suggest that the clinical application of oncolytic viruses is likely to be impacted by the unique metabolic state of the tumor microenvironment and that myeloid-derived suppressor cell-mediated depression of arginine within tumors may play a critical role in suppressing these treatments.

Keywords:  MT: Regular Issue; arginine metabolism; immunotherapy; myxoma virus; oncolytic virotherapy

DOI:  https://doi.org/10.1016/j.omton.2025.201066
Biomolecules. 2025 Sep 26. pii: 1369. [Epub ahead of print]15(10):

Research Advances in Cancer-Associated Fibroblasts in Prostate Cancer Progression.

Zhonghao Tang, Si Shen, Chenwei Gu, Sixin Li, Yan Qin, Yuanyuan Mi.

  The tumor microenvironment (TME) is crucial for tumor growth and progression, within which cancer-associated fibroblasts (CAFs) play a central role in regulating cancer cell proliferation, metastasis, and therapy resistance through various mechanisms. Although early-stage prostate cancer (PCa) has a high cure rate, advanced disease often becomes difficult to manage due to resistance to standard therapies such as androgen deprivation therapy (ADT). Therefore, a deep understanding of the interaction mechanisms between CAFs and PCa cells is essential for developing novel therapeutic strategies targeting resistant advanced PCa. This review systematically summarizes key signaling pathways and molecular mechanisms through which CAFs promote PCa progression, as recently discovered, evaluates the potential of CAFs as prognostic biomarkers, and discusses novel CAF-based therapeutic targets and intervention strategies for PCa.

Keywords:  cancer-associated fibroblasts; prostate cancer; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/biom15101369
Front Oncol. 2025 ;15 1704061

Editorial: Interplay of immunity and ECM in cancer.

Albina Fejza, Federica Benvenuti, Eva Andreuzzi.



Keywords:  biomarkers; cancer; extracellar matrix; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1704061
Nat Immunol. 2025 Oct 29.

Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.

Haoxin Zhao, Jaeoh Park, Yuzhu Wang, Yi-Ju Chou, Lemin Li, Lydia N Raines, Michael Hsu, Ching-Cheng Lin, Wei Cao, Yuli Ouyang, Heng-Yi Chen, Linghua Zheng, Zihai Li, Alex Y Huang, Ping-Chih Ho, Chan-Wang Jerry Lio, Stanley Ching-Cheng Huang.

Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41590-025-02324-2
Cell Biol Toxicol. 2025 Oct 31. 41(1): 146

HypoxamiRs in pancreatic cancer: master regulators of the hypoxic tumor microenvironment.

Pooria Salehi-Sangani, Amir Hosein Maharati, Bahareh Payami, Mohsen Aliakbarian, Mohammad Reza Abbaszadegan.

  Pancreatic cancer (PC) is characterized by aggressive progression, chemoresistance, and immune evasion, largely driven by its hypoxic tumor microenvironment (TME). The extensive desmoplastic reaction in PC, characterized by dense stromal fibrosis, exacerbates hypoxia by impairing blood flow, creating a hostile environment that limits therapeutic efficacy. Hypoxia-induced microRNAs (HypoxamiRs) have emerged as critical regulators of these processes, modulating cellular pathways that promote tumor survival and therapy resistance. HypoxamiRs exert their effects by interacting with hypoxia-inducible factors, including HIF-1α and HIF-2α. Beyond their direct impact on tumor cells, HypoxamiRs modulate the behavior of immune and stromal cells within the hypoxic TME. Key contributors to hypoxia, such as cancer-associated fibroblasts, pancreatic stellate cells, macrophages, and natural killer (NK) cells, facilitate HypoxamiR transfer via exosomes. This review explores the multifaceted roles of HypoxamiRs in key processes such as immune modulation, chemoresistance, epithelial-mesenchymal transition (EMT), autophagy, angiogenesis, and apoptosis in pancreatic cancer. We also highlight the complex interplay between HypoxamiRs and other non-coding RNAs (ncRNAs) in regulating hypoxia-driven pathways. Investigating these complex interactions provides critical insights for developing novel therapeutic strategies to overcome chemoresistance and immune evasion in pancreatic cancer.

Keywords:  Chemo-resistance; Hypoxia; MiRNA; Pancreatic ductal adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10565-025-10092-w
Cell Commun Signal. 2025 Oct 30. 23(1): 468

Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.

Yan Xu, Jiafeng Wang, Aixiang Wu, Mengchuan Wang.

  Ammonia has long been regarded as the end-toxic product of hepatic metabolism. Under normal physiological conditions, ammonia is metabolized through the urea cycle; however, its metabolic imbalance is closely related to various diseases, including hepatic encephalopathy, liver fibrosis, and cancer. Ammonia-induced cell death, specifically the selective death of immune cells, has emerged in recent years as a new form of cell death in the field of tumor biology, offering a new perspective on the regulation of tumor cell fate. This review creatively focuses on the role of ammonia in tumorigenesis, development, and treatment resistance. We systematically reviewed the sources and dynamic balance of ammonia in the tumor microenvironment and found that it plays a key role in tumor metabolic reprogramming by regulating glutamine metabolism, mitochondrial function, and lysosomal stability in tumor cells. Ammonia can also induce the selective death of immune cells, reshape the immune cell map in the tumor microenvironment, and regulate the anti-tumor immune response. Mechanistically, we analyzed the multi-level network of ammonia metabolism regulation, including the role of glutamine synthetase, the mTOR signaling pathway, and epigenetic modification in ammonia death. In addition, this review emphasizes the importance of ammonia as a potential target for cancer therapy and proposes multimodal strategies combining metabolic regulation and immunotherapy to achieve precision in cancer treatment. Finally, the comprehensive map of ammonia in the tumor ecosystem was constructed, highlighting its potential clinical value as a new anti-cancer target.

Keywords:  Ammonia; Apoptosis; Autophagy; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-025-02504-5