bims-flamet 2025-11-23 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–11–23
24 papers selected by
Peio Azcoaga, Biodonostia HRI

TREM2-mediated regulation of myeloid cells in the tumor microenvironment: new insights and therapeutic prospects.
Recent progress in immune evasion mechanisms of triple-negative breast cancer.
Emerging Role of MDSCS as Novel Biomarkers and Therapeutic Targets for Cancer Immunotherapy.
Immunological landscape of colorectal cancer: tumor microenvironment, cellular players and immunotherapeutic opportunities.
IFI30 promotes tumor-associated macrophage infiltration via activation of the ATF3-CCL5 axis in breast cancer.
Macrophage-targeted immunocytokine leverages myeloid, T, and NK cell synergy for cancer immunotherapy.
Targeting the Dynamics Between TAMs and CAR-T Cells in Solid Tumor Therapies.
Epithelial-mesenchymal transition and tumor-associated macrophage axis in metastatic breast cancer: converging mechanisms and therapeutic perspectives.
CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.
Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma.
Unlocking the tumor microenvironment: Innovative strategies for cancer therapy and translational insights.
Multimodal cell-cell communication driving CD8+ T cell dysfunction and immune evasion.
Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.
Lipid droplets in the tumor microenvironment: Biogenesis, functional diversity, and therapeutic targeting.
Advancements in research regarding the influence of the tumor microenvironment on the proliferation and metastasis of osteosarcoma (Review).
Mitochondria-targeted strategies in tumor immunity.
Ammonia in cancer: dual roles and therapeutic strategies.
Chimeric antigen receptor T-cell therapy for solid tumors: A review of the intricate mechanisms and potential strategies.
Engineering the tumor microenvironment: oncolytic NDV to facilitate CAR-T cell therapy.
Cancer-Associated Fibroblasts Promote Imatinib Resistance in Gastrointestinal Stromal Tumors through PGK1-Mediated Metabolic Reprogramming.
Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment.
Collagen-Based Tumor Spheroid Model for Investigating Tumor-Macrophage Interactions through Extracellular Matrix Remodeling.
Hydrostatic pressure from basal side promotes cancer proliferation, enhances migration and alters cell polarity: a model of the effects of interstitial fluid pressure in tumor microenvironment.
C-X-C chemokine receptor CXCR4 mediates diurnal changes in the aggregation and dispersion of CD8+ T cells within the tumor microenvironment.

NPJ Precis Oncol. 2025 Nov 18. 9(1): 359

TREM2-mediated regulation of myeloid cells in the tumor microenvironment: new insights and therapeutic prospects.

Yueyu Huang, Wanxia Fang.

Triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a key regulator of myeloid cell function within the tumor microenvironment (TME). Accumulating evidence indicates that TREM2-expressing tumor-associated macrophages and myeloid-derived suppressor cells promote immunosuppression, tumor progression, and resistance to immunotherapy. Through modulation of cellular metabolism, antigen presentation, and cytokine secretion, TREM2 signaling critically shapes tumor immune dynamics. Owing to this central role, TREM2 has emerged as a promising immunotherapeutic target. Preclinical and clinical studies demonstrate that TREM2 blockade can reprogram the immunosuppressive TME, enhance T-cell infiltration, and augment the efficacy of immune checkpoint inhibitors. This review synthesizes current knowledge of the molecular mechanisms underlying TREM2 signaling in myeloid cells, its influence on TME remodeling, and its potential as both a biomarker and therapeutic target in cancer immunotherapy. Finally, we highlight current challenges and future perspectives in harnessing TREM2-directed strategies to counteract tumor immune evasion.

DOI: https://doi.org/10.1038/s41698-025-01152-9
J Transl Med. 2025 Nov 18. 23(1): 1314

Recent progress in immune evasion mechanisms of triple-negative breast cancer.

Yiyan Yang, Weidong Wang.

  Significant progress has been made in understanding the complex immune evasion mechanisms of triple-negative breast cancer (TNBC), paving the way for more effective immunotherapies. This review highlights key advances in elucidating the molecular basis of TNBC immune escape, including aberrant immune checkpoint expression, metabolic reprogramming, epigenetic regulation, immune evasion by associated cellular components, and clinical trials of emerging immunotherapies. Specifically, overexpression of immune checkpoint inhibitors such as PD-L1 on TNBC cells and within the tumor microenvironment (TME) plays a critical role in suppressing antitumor immunity. Secondly, TNBC cells evade immune surveillance through metabolic reprogramming. For instance, upregulated glutamine metabolism supports tumor growth and modulates the TME toward immunosuppression by limiting nutrient availability to immune cells. Competitive consumption of amino acids such as tryptophan and arginine further compromises immune cell function, promoting immune escape. Epigenetic modifications, including DNA methylation and histone modifications, are increasingly recognized as key contributors to immune evasion in TNBC. These mechanisms can silence genes involved in antigen presentation and immune activation while promoting the expression of immunosuppressive factors. Long non-coding RNAs (lncRNAs) have been identified as central regulators of immune evasion in TNBC, offering new therapeutic targets for intervention. Moreover, TNBC actively shapes its microenvironment to establish immunosuppression, including recruitment of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-polarized macrophages, which collectively inhibit effector T cell function. Building on these mechanistic insights, this review also integrates findings from clinical trials evaluating next-generation immunotherapies, including bispecific antibodies targeting PD-1/CTLA-4, LAG-3 inhibitors, and CD47-SIRPα blockers, as well as potential biomarkers. These novel combination strategies aim to overcome resistance to single-agent checkpoint inhibitors, while research explores monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs) within biomarker-driven personalized treatment frameworks. The ultimate goal is to improve survival and quality of life for TNBC patients through tailored immunotherapies.

Keywords:  Immune evasion; Immunosuppression; Immunotherapy; Triple negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07370-w
Immunotargets Ther. 2025 ;14 1267-1291

Emerging Role of MDSCS as Novel Biomarkers and Therapeutic Targets for Cancer Immunotherapy.

S Silva-Romeiro, Rocio Del Carmen Flores-Campos, María Luisa Sánchez-León, V Sánchez-Margalet, Luis De la Cruz-Merino.

  Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate under pathological conditions such as cancer, where they contribute to immune evasion, tumor progression, and resistance to therapy. These cells exert potent immunosuppressive effects by inhibiting T cell activation, inducing regulatory T cells, modulating antigen-presenting cells, and shaping an immunosuppressive tumor microenvironment (TME). Their suppressive functions involve multiple mechanisms, including amino acid depletion, production of reactive oxygen and nitrogen species, expression of immune checkpoint ligands, and secretion of immunoregulatory cytokines such as IL-10 and TGF-β. Besides these immune-related roles, MDSCs also promote tumor growth through non-immunological mechanisms, including the stimulation of angiogenesis and undergoing metabolic reprogramming. These adaptations support their survival and function in the hostile TME. Given their multifaceted role in cancer, MDSCs represent a promising target for therapeutic intervention. Furthermore, their abundance and dynamic modulation during treatment confer them tremendous potential as biomarkers to monitor therapy efficacy and stratify patients. This review provides a comprehensive overview of MDSC biology, their mechanisms of action, and their emerging clinical relevance as biomarkers and therapeutic targets. We also explore current strategies aimed at targeting MDSCs, including their depletion, inhibition of recruitment, functional blockade, and promotion of their differentiation into mature myeloid cells. Integrating these approaches with existing cancer therapies holds great promise for enhancing antitumor immunity and overcoming resistance in both solid tumors and hematologic malignancies.

Keywords:  immune biomarkers; immunotherapy; myeloid-derived suppressor cells; tumor microenvironment

DOI:  https://doi.org/10.2147/ITT.S485642
Front Mol Biosci. 2025 ;12 1687556

Immunological landscape of colorectal cancer: tumor microenvironment, cellular players and immunotherapeutic opportunities.

Adile Buse Andac-Aktas, Gizem Calibasi-Kocal.

  Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with outcomes shaped not only by genetic alterations but also by the complexity of the tumor microenvironment (TME). The TME encompasses stromal and endothelial cells, extracellular matrix components, gut microbiota, and a diverse array of immune cells that dynamically interact to influence tumor initiation, progression, and therapeutic response. This review delineates the immunological landscape of CRC, highlighting the dual functions of innate immune cells-including tumor-associated macrophages, natural killer cells, dendritic cells, neutrophils, and mast cells-and adaptive immune players such as cytotoxic T lymphocytes, helper T-cell subsets, and B/plasma cells. These cellular interactions contribute to the heterogeneity between immunologically "hot" microsatellite instability-high (MSI-H) tumors, which are highly responsive to immunotherapy, and "cold" microsatellite-stable (MSS) tumors, which remain resistant. Key mechanisms of immune evasion, such as cancer immunoediting, checkpoint signaling, and exosome-mediated communication, are examined alongside prognostic tools like the Immunoscore that serve as biomarkers of immune infiltration. Emerging immunotherapeutic strategies, including checkpoint blockade, macrophage reprogramming, natural killer cell agonists, and microbiome modulation, are discussed with emphasis on both their promise and limitations in CRC management. By integrating current insights into immune-tumor interactions, the review underscores opportunities for developing personalized, TME-targeted interventions to improve CRC outcomes.

Keywords:  colorectal cancer; immunity; immunological heterogeneity; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2025.1687556
Innovation (Camb). 2025 Nov 03. 6(11): 101005

IFI30 promotes tumor-associated macrophage infiltration via activation of the ATF3-CCL5 axis in breast cancer.

Liwen Ren, Yihui Yang, Wan Li, Xiangjin Zheng, Jinyi Liu, Sha Li, Hong Yang, Yizhi Zhang, Hongquan Wang, Guanhua Du, Xifu Wang, Jinhua Wang.

  Immunotherapy has transformed cancer treatment, but its effectiveness in breast cancer remains suboptimal. Tumor-associated macrophages (TAMs), a key component of the tumor microenvironment (TME), contribute significantly to immune evasion. In this study, we identified gamma-interferon-inducible lysosomal thiol reductase (IFI30) as a critical regulator of TAM function in breast cancer. IFI30 expression is upregulated in breast cancer via enhanced Histone 3 lysine 27 acetylation (H3K27ac) modification and promotes tumor progression and metastasis in an immune-dependent manner. Mechanistically, IFI30 in breast cancer cells recruits TAMs by activating the ATF3-CCL5 axis. Within macrophages, it promotes M2-like polarization and PD-L1 upregulation, fostering an immunosuppressive TME. Our findings established IFI30 as a promising therapeutic target for disrupting TAM-mediated immune suppression and enhancing breast cancer immunotherapy.

Keywords:  H3K27ac; IFI30; breast cancer; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.xinn.2025.101005
Cell. 2025 Nov 19. pii: S0092-8674(25)01235-8. [Epub ahead of print]

Macrophage-targeted immunocytokine leverages myeloid, T, and NK cell synergy for cancer immunotherapy.

Michelle von Locquenghien, Pascale Zwicky, Ken Xie, Diego Adhemar Jaitin, Fadi Sheban, Adam Yalin, Florian Uhlitz, Chamutal Gur, Reut Sharet Eshed, Eyal David, Kfir Mazuz, Caroline Jennings Marin, Ankita Sankar, Devin Mediratta, Roberto Avellino, Assaf Weiner, Ido Amit.

  Tumor-associated macrophages (TAMs) expressing the myeloid checkpoint TREM2 are key immunosuppressive cells in the tumor microenvironment (TME), driving tumor progression and contributing to poor prognosis in cancer patients. Due to their pivotal role, TAMs have emerged as a promising target for immunotherapies. However, current TAM-targeting monotherapies show limited efficacy, highlighting the need for strategies engaging multiple immune modalities. Here, we developed myeloid-targeted immunocytokines and natural killer (NK)/T cell enhancers (MiTEs) harnessing myeloid and lymphoid synergy for immunotherapy. MiTEs are trans-acting immunocytokines with tumor-specific activation, allowing dual targeting of TAMs and lymphocytes by TREM2 antagonism and cytotoxic effector cell activation through interleukin (IL)-2. To avoid off-target toxicities, MiTEs contain an IL-2 masking moiety, which is cleaved by a TAM-specific protease. MiTEs demonstrate high efficacy in preclinical tumor models through extensive immune reprogramming spanning TAM, T, and NK cell compartments. MiTEs show transformative potential for treating solid cancers by inducing potent multi-axis anti-tumor immunity while minimizing toxicities.

Keywords:  T and NK cell synergy; TME-conditional IL-2; TREM2; cancer immunotherapy; cytokines; myeloid checkpoints; myeloid-targeted immunocytokine; single-cell genomics; synthetic immunology; tumor-associated macrophages; tumor-microenvironment modulation

DOI:  https://doi.org/10.1016/j.cell.2025.10.030
Adv Sci (Weinh). 2025 Nov 21. e15700

Targeting the Dynamics Between TAMs and CAR-T Cells in Solid Tumor Therapies.

Xiang Zhang, Hao Zheng, Zi-Chang Liu, Ling-Jie Luo, Xiao Dong, Xin-Gang Cui, Yan-Wei Wu, Liang Chen.

  Although CAR T-cell therapy has transformed treatment outcomes for patients with haematological malignancies, the existing barriers in solid tumors treatment remain due to TAM immunosuppression. This review explores the work of others on the interplay between M2-like immunosuppressive TAMs and CAR-T cells in the tumor microenvironment. The ways TAMs impair the effector functions of CAR-T cells are described mediated by secretion of cytokines, immune checkpoints, metabolites, and detrimental post-translational modification. New concept therapeutic approaches are designed to these interactions for improving the efficacy of CAR-T cells in solid tumors. With an emphasis on novel strategies to counteract TAM immunosuppression, this review aims to reshape the perspective on the utility and effectiveness of CAR-T therapy in solid tumors and, consequently, extend the reach of a highly promising therapeutic approach.

Keywords:  CAR‐T cells; solid tumors; tumor microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202515700
Life Sci. 2025 Nov 14. pii: S0024-3205(25)00720-9. [Epub ahead of print] 124084

Epithelial-mesenchymal transition and tumor-associated macrophage axis in metastatic breast cancer: converging mechanisms and therapeutic perspectives.

Christina E Wheeler, Samy Lamouille.

  Breast cancer is a leading cause of cancer-related death in women worldwide, mainly attributable to metastatic progression accounting for about 90 % of these fatalities. The metastatic cascade can be initiated by epithelial-mesenchymal transition (EMT), a molecular and cellular program in which cancer cells lose their cell-cell junctions and acquire a more invasive phenotype. EMT is induced by a range of signaling molecules and growth factors, contributing significantly to the metastatic capability of cancer cells. Within the tumor microenvironment, tumor-associated macrophages (TAMs) can promote EMT through secretion of such molecules including chemokines, Wnt, IL-6, and TGF-β. Additionally, tumor cells secrete chemokines that drive the differentiation of macrophages toward an anti-inflammatory, pro-tumorigenic phenotype. This alliance between breast cancer cells and TAMs increases tumorigenicity and facilitates metastasis, highlighting a critical field of study for the development of novel and more efficient treatments in breast cancer. In this review, we discuss the mechanisms of TAM and EMT interaction in breast cancer progression and metastasis, and potential therapeutic approaches to target this crosstalk.

Keywords:  Breast cancer; Epithelial-mesenchymal transition; Metastasis; Signaling pathways; Therapeutics; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.lfs.2025.124084
Autoimmunity. 2025 Dec;58(1): 2579069

CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.

Hai Rong Li, Jie Xiong, Chun Hui Wang, Li Bing Hu, Ying Bao Wang, Qin Rong Ping, Meng Yang, Jun Tan, Ting Ting Li, Yang Yang.

  The advent of chimeric antigen receptor (CAR) T cell therapy has yielded transformative efficacy in hematological malignancies, yet its application in solid tumors remains constrained by the immunosuppressive tumor microenvironment (TME). Characterized by hypoxia, acidosis, and nutrient deprivation, the TME critically compromises CAR-T cell infiltration, persistence, and effector functions. Hypoxia-inducible factor 1α (HIF-1α), a central regulator of cellular adaptation to hypoxia within the TME, modulates T cell metabolism and functionality-presenting a strategic framework for enhancing CAR-T cell efficacy in solid malignancies. This review characterizes the role of HIF-1α in reprogramming the tumor-immune microenvironment, with specific emphasis on its metabolic regulation of T cells and translational implications for CAR-T therapy. Under hypoxic stress, HIF-1α orchestrates a metabolic shift toward glycolysis in effector T cells by suppressing oxidative phosphorylation (OXPHOS) while upregulating key glycolytic enzymes (e.g. GLUT1, HK2, LDHA). This adaptation sustains ATP production while attenuating mitochondrial reactive oxygen species (ROS) accumulation, thereby mitigating T cell exhaustion and augmenting cytotoxic persistence. This HIF-1α-mediated metabolic reprogramming provides critical insights for overcoming barriers to CAR-T cell efficacy in solid tumors.

Keywords:  CAR-T cells; HIF-1α; immunotherapy; solid tumor treatment; tumor microenvironment

DOI:  https://doi.org/10.1080/08916934.2025.2579069
Biomed Pharmacother. 2025 Nov 20. pii: S0753-3322(25)01000-5. [Epub ahead of print]193 118806

Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma.

Chalermchai Somboonpatarakun, Nattaporn Phanthaphol, Kwanpirom Suwanchiwasiri, Boonyanuch Ramwarungkura, Pa-Thai Yenchitsomanus, Mutita Junking.

  Cholangiocarcinoma (CCA) is an aggressive epithelial malignancy characterized by poor prognosis, limited treatment options, and high recurrence rates even after surgery. Chimeric antigen receptor (CAR) T cell therapy has achieved notable success in hematologic malignancies, but its efficacy in solid tumors such as CCA is hindered by the immunosuppressive tumor microenvironment, particularly through PD-1/PD-L1 axis. To address these barriers, we developed a sixth-generation CAR T cell, A20 CAR6, incorporating the A20 peptide, a high-affinity ligand for integrin αvβ6-a tumor-associated antigen frequently overexpressed in CCA. Beyond antigen targeting, A20 CAR6 T cells are engineered to secrete a bispecific protein engager (BiPE) that binds PD-L1 on tumor cells and CD3 on T cells. This dual-function design aims to neutralize PD-L1-mediated immune suppression and recruit both CAR and bystander T cells to enhance tumor killing. Compared with conventional fourth-generation A20 CAR4 T cells lacking BiPE secretion, A20 CAR6 T cells exhibited superior cytotoxicity, cytokine production, and proliferation against integrin αvβ6+/PD-L1+ CCA cells. Notably, the secreted αPD-L1/αCD3 BiPE augmented CAR T cell activity and redirected non-engineered T cells to target tumor cells, amplifying the overall anti-tumor response. These findings suggest that A20 CAR6 T cells represent a promising next-generation immunotherapy with the potential to overcome key resistance mechanisms in CCA and improve treatment outcomes.

Keywords:  Bi-specific protein engager; CAR T cell therapy; Cholangiocarcinoma; Integrin αvβ6; Programmed death-ligand 1

DOI:  https://doi.org/10.1016/j.biopha.2025.118806
Cell Rep Med. 2025 Nov 18. pii: S2666-3791(25)00541-5. [Epub ahead of print]6(11): 102468

Unlocking the tumor microenvironment: Innovative strategies for cancer therapy and translational insights.

Elisa Panada, Tatyana Kuznetsova, Sara Hamilton.

DOI: https://doi.org/10.1016/j.xcrm.2025.102468
Front Immunol. 2025 ;16 1691746

Multimodal cell-cell communication driving CD8+ T cell dysfunction and immune evasion.

Liping Chen, Qianping Huang, Peipei Zhou.

  Effective anti-tumor immunity critically depends on functional CD8+ T cells, yet in almost all solid tumors, these cells become dysfunctional, exhausted, or spatially excluded. This breakdown of immune surveillance arises not only from cell-intrinsic T cell exhaustion but also from multimodal communication among tumor, stromal, and immune cells within the tumor microenvironment (TME). This communication is mediated not only through direct receptor-ligand interactions but also through a suite of indirect mechanisms, such as metabolic competition, secretion of immunosuppressive metabolites and cytokines, extracellular vesicle exchange, and even mitochondrial transfer via tunneling nanotubes or membrane transfer through T cell trogocytosis. Together, these suppressive interactions impair CD8+ T cell metabolism, effector function, and persistence, thereby enabling tumor immune evasion. In this review, we summarize current understanding of how multimodal cell-cell communication, including immune checkpoints, metabolic reprogramming, and stromal crosstalk, cooperatively drive CD8+ T cell dysfunction. We also highlight emerging therapeutic strategies aimed at rewiring these suppressive networks, with emphasis on translational potential. A deeper understanding of the spatial, molecular, and metabolic context of CD8+ T cell suppression offers new avenues to enhance the efficacy of cancer immunotherapies.

Keywords:  CD8+ T cell; dysfunction; multimodal cell-cell communication; suppression; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1691746
Trends Cell Biol. 2025 Nov 15. pii: S0962-8924(25)00245-4. [Epub ahead of print]

Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.

Takamasa Ishino, Yu Inutsuka, Hideki Ikeda, Yosuke Togashi.

  Mitochondria are organelles that are essential for their multiple roles in cell biology, including energy metabolism. Accumulating evidence has revealed that intercellular mitochondrial transfer occurs within the tumor microenvironment (TME). The mitochondrial transfer among the TME components can profoundly affect tumor progression, immune surveillance, and stromal remodeling. Importantly, cancer cells function not only as recipients but also as donors of mitochondria, underscoring the bidirectional nature of this process. This review summarizes the multifaceted roles of mitochondria in cancer cells, immune cells, and stromal cells, with particular emphasis on emerging insights into mitochondrial transfer. In addition, the current implications of mitochondria-targeting therapies and future challenges in this evolving field are highlighted.

Keywords:  antitumor immunity; cancer; mitochondria; mitochondrial transfer

DOI:  https://doi.org/10.1016/j.tcb.2025.10.004
Chin Med J (Engl). 2025 Nov 20.

Lipid droplets in the tumor microenvironment: Biogenesis, functional diversity, and therapeutic targeting.

Jinghan Zhong, Yuqi Liu, Chenshiyu Wang, Shuyi Li, Xiu-Wu Bian, Yi-Fang Ping.

   ABSTRACT: Historically regarded as inert energy storage depots, lipid droplets (LDs) are now recognized as dynamic organelles that regulate diverse cellular processes, including membrane biosynthesis, stress adaptation, signal transduction, and metabolic homeostasis. In cancer, tumor cells hijack LD-driven metabolic pathways to fuel uncontrolled proliferation, migration, and therapy resistance, thereby promoting tumor progression. Emerging evidence suggests that tumor-associated immune cells similarly utilize LD-mediated mechanisms to reinforce immunosuppression and support tumor progression. However, the intercellular crosstalk and regulatory networks coordinated by LD-associated effectors across malignant and immune cells have not been systematically explored. This review synthesizes current knowledge on LD biogenesis, spatiotemporal distribution, and microenvironment-dependent regulation in both tumor cells and tumor-infiltrating immune cells. We focus on how LD-associated proteins shape the immunosuppressive tumor microenvironment and drive oncogenic progression. Furthermore, we highlight novel therapeutic strategies targeting LD metabolism to simultaneously disrupt tumor survival and counteract immune cell-mediated protumorigenic effects. Finally, we discuss the challenges and future directions of LD-targeted therapies, particularly in combination with immunotherapies, to provide a roadmap for next-generation anticancer interventions.

Keywords:  Lipid droplets; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment; Tumor-infiltrating immune cells

DOI:  https://doi.org/10.1097/CM9.0000000000003916
Oncol Lett. 2026 Jan;31(1): 20

Advancements in research regarding the influence of the tumor microenvironment on the proliferation and metastasis of osteosarcoma (Review).

Tao Shi, Jianping Kang, Qiyang Wang, Jiamei Song, Xiaofeng He.

  Osteosarcoma (OS), a common primary malignant bone tumor in children and young adults, is significantly influenced by a complex tumor microenvironment (TME) that includes bone cells, stromal cells, vascular cells, immune cells and a mineralized extracellular matrix (ECM). In recent years, the role of the TME in OS progression has garnered increasing attention. The TME not only provides the physical and biochemical support necessary for tumor cell growth, invasion and metastasis, but also promotes the maintenance of the malignant tumor phenotype through mechanisms such as immune suppression, angiogenesis and metabolic reprogramming. The present review discusses how various cellular and non-cellular components within the OS TME interact to drive tumor progression. Consequently, targeting the TME has emerged as a promising therapeutic strategy to overcome the limitations of conventional treatments, particularly for metastatic or recurrent OS. The present review underscores the potential of TME-targeted therapies and highlights the need for further research into the heterogeneity of the TME to improve clinical outcomes.

Keywords:  bone marrow mesenchymal stem cells; extracellular matrix; hypoxia; osteosarcoma; tumor microenvironment; tumor- associated immune cells

DOI:  https://doi.org/10.3892/ol.2025.15373
Front Immunol. 2025 ;16 1646138

Mitochondria-targeted strategies in tumor immunity.

Xudong Cheng, Yian Wang, Bryon Johnson, Ming You.

  Mitochondria, as regulators of cellular energy production and metabolism, play a crucial role in tumor growth and survival. Tumors are reprogrammed to accommodate rapid proliferation through the Warburg effect. This reprogramming leads to the accumulation of metabolites such as lactate and ketone bodies, thereby lowering the pH of the tumor microenvironment, inhibiting the activity of effector T cells and NK cells, while promoting the infiltration of regulatory T cells and MDSCs, forming an immunosuppressive microenvironment. ROS produced by mitochondria can affect immune cell function by modulating their signaling pathways. Mitochondria also release DAMPs, which activate the antigen-presenting capacity of dendritic cells and initiate anti-tumor immune responses. Currently, various methods have been employed, such as DLCs modifications and mitochondrial targeted delivery, which enable drugs to penetrate the lipid bilayer and enter the mitochondria, thereby helping to reduce immunosuppression in the tumor microenvironment. In this review, we will discuss the impact of mitochondria on tumor immunity, strategies to target tumor cell mitochondria, and progress on the discovery of mitochondria-targeted drugs to enhance tumor immunity, providing potential directions for developing new cancer therapeutic strategies.

Keywords:  TME; cancer; immunotherapy; mitochondria targeted; triphenylphosphonium

DOI:  https://doi.org/10.3389/fimmu.2025.1646138
Cancer Cell Int. 2025 Nov 21. 25(1): 420

Ammonia in cancer: dual roles and therapeutic strategies.

Jinhui Wei, Yue Chen, Quanzhang Li, Fuxin Huang, Chuanzhao Zhang, Baohua Hou, Shanzhou Huang.

  Ammonia, a toxic nitrogenous metabolic byproduct, has garnered increasing attention for its pivotal role in tumor biology. The human body has developed intricate detoxification mechanisms to regulate ammonia homeostasis and maintain acid‒base equilibrium. Through their adaptation mechanisms, cancer cells can exploit ammonia to facilitate their growth and modulate the tumor immune microenvironment. As ammonia is a toxic substance, it can have a toxic effect on tumor, thereby inhibiting tumor growth. This article critically examines the sources and destinations of ammonia within the tumor microenvironment (TME), offering an innovative synthesis of its dual roles in both promoting and inhibiting tumor progression. Additionally, it explores therapeutic strategies targeting ammonia metabolism and anticipates future research trajectories, thereby providing valuable insights and a theoretical framework for ammonia-based therapies in oncology.

Keywords:  Ammonia; Cancer; Dual roles; Therapies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-04065-6
Int Immunopharmacol. 2025 Nov 13. pii: S1567-5769(25)01826-0. [Epub ahead of print]168(Pt 1): 115838

Chimeric antigen receptor T-cell therapy for solid tumors: A review of the intricate mechanisms and potential strategies.

Swati Arora, Pranshul Sethi, Adrita Banerjee, Md Khokon Miah Akanda, Mohamed S Abd El Hafeez, Sanzia Mehjabin, Keshav S Moharir, Swati Mohanty, Sumit Sheoran.

  Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized cancer immunotherapy, achieving remarkable success in hematological malignancies. However, its clinical application to solid tumors is hindered by significant challenges, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and physical barriers that limit effective T-cell infiltration. This review examines the intricate mechanisms of CAR-T therapy, with a focus on T-cell engineering, activation, and tumor targeting, highlighting the interplay between therapeutic design and tumor-specific complexities. The barriers unique to solid tumors, such as immune evasion mediated by suppressive cytokines and regulatory cells, tumor antigen escape, and the resilience of the extracellular matrix, are critically analyzed. Innovative strategies, including multi-antigen targeting constructs, logic-gated CARs for tumor-selective activation, and armored CAR-T cells equipped to counteract immunosuppressive signals, are evaluated for their potential to enhance therapeutic efficacy. Furthermore, the incorporation of matrix-degrading enzymes and immune checkpoint inhibitors is discussed as a means to overcome physical and immune-mediated resistance. Emerging targets such as B7-H3, Claudin 18.2, and MUC1, along with advancements in companion diagnostics, are reshaping the landscape of CAR-T therapy by enabling more precise patient selection and real-time therapeutic monitoring. This review synthesizes recent progress and persisting challenges, aiming to provide a comprehensive framework for advancing CAR-T therapy into a transformative modality for the treatment of solid tumors.

Keywords:  CAR-T cells; Immune checkpoint inhibitors; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2025.115838
J Transl Med. 2025 Nov 19. 23(1): 1316

Engineering the tumor microenvironment: oncolytic NDV to facilitate CAR-T cell therapy.

Mei Wang, Ke Jiang, Alexandra Aicher, Christopher Heeschen.

  Chimeric antigen receptor (CAR)-T cell therapy has achieved significant progress in the treatment of hematologic cancers but continues to face major obstacles in solid tumors, including antigen heterogeneity, limited infiltration, and an immunosuppressive tumor microenvironment (TME). Oncolytic viruses (OVs) have emerged as promising tools to reshape the TME and improve CAR-T cell activity, yet many OVs encounter translational hurdles due to human seroprevalence and safety concerns. Newcastle disease virus (NDV), a naturally tumor-selective avian paramyxovirus, offers unique advantages as a non-integrating, non-pathogenic platform with a longstanding veterinary safety record and minimal pre-existing immunity in humans. NDV mediates direct oncolysis and immunogenic cell death, while simultaneously activating dendritic cells, repolarizing macrophages, and enhancing immune cell recruitment, thereby creating a TME that is more permissive to CAR-T cell therapy. Recent advances have enabled NDV to deliver immunostimulatory payloads locally within tumors, offering synergistic combinations to address CAR-T cell exhaustion and persistence. Looking ahead, further engineering efforts may expand the potential of this combined approach. This review summarizes the biological rationale, preclinical evidence, and translational prospects for integrating NDV with CAR-T cell therapy to improve outcomes in solid tumors.

Keywords:  CAR-T cell therapy; Immunomodulation; Immunotherapy; Newcastle disease virus; Oncolytic virus; Tumor microenvironment; Virotherapy

DOI:  https://doi.org/10.1186/s12967-025-07342-0
Cancer Res. 2025 Nov 21.

Cancer-Associated Fibroblasts Promote Imatinib Resistance in Gastrointestinal Stromal Tumors through PGK1-Mediated Metabolic Reprogramming.

Chao Li, Tianhong Teng, Xiaohan Lin, Xiangfei Sun, Tuo Yi, Hongshan Wang, Xiaodong Gao, Kuntang Shen.

Gastrointestinal stromal tumors (GISTs), the most common sarcomas of the gastrointestinal tract, are primarily driven by c-KIT or PDGFRA mutations that activate downstream signaling pathways, including PI3K/AKT/mTOR. While imatinib, a first-line tyrosine kinase inhibitor (TKI), is initially effective, resistance develops in ~50% of patients within 20 months. Second- and third-line TKIs, such as sunitinib and regorafenib, provide limited benefits, highlighting the urgent need to address resistance mechanisms. Previous research has predominantly focused on genetic drivers of resistance and overlooked the role of the tumor microenvironment (TME). Here, we identified a role for cancer-associated fibroblasts (CAFs) in driving imatinib resistance. Specifically, TGF-β1 secreted by CAFs amplified CCN2/Rack1 signaling. The CCN2/Rack1 axis activated PI3K/AKT signaling to induce phosphorylation and mitochondrial translation of PGK1, promoting metabolic reprogramming that supported tumor survival and drug resistance. Co-culture models and single-cell RNA sequencing revealed distinct CAF subtypes and showed that CAF-secreted TGF-β1 enhanced glycolysis and inhibited the tricarboxylic acid (TCA) cycle, fueling GIST progression and secondary resistance. Inversely, CCN2 secreted by GIST cells promoted TGF-β1 production in CAFs. These findings uncover a TGF-β1/CCN2/Rack1/PGK1 mechanism linking CAF-mediated metabolic reprogramming to imatinib resistance in GISTs. Targeting CAF-GIST interactions and key metabolic pathways presents a promising therapeutic strategy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1404
Acta Biochim Biophys Sin (Shanghai). 2025 Nov 20.

Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment.

Xiaoyang Sun, Lulu Qin, Xinghua Liang, Dongrui Wang.

  Immunotherapy, including cellular therapy, has emerged as a crucial pillar in cancer treatment, complementing established modalities such as surgery, chemotherapy and radiotherapy. The clinical observation that immunotherapy is effective in only a limited proportion of patients inspires mechanistic research on the complicated regulatory network within the tumor microenvironment (TME). Circadian regulation significantly affects immune cell behavior, including the activity of immune cells and cytokine production, and emerging evidence suggests the key role of circadian regulation in the TME, which subsequently affects the effectiveness of immunotherapy. Results from preclinical and clinical studies indicate that appropriate timing of adoptive cellular therapy and immune checkpoint blockade therapy improves their efficacy. Therefore, understanding the molecular mechanism of the circadian rhythm together with its role in immunotherapy is essential for optimizing cellular function, proliferation and persistence in the TME. Here, we review how circadian rhythms influence immunotherapy and the TME across different stages of tumor progression. Future clinical protocols may integrate concepts of circadian rhythm and immunotherapy to enhance treatment response.

Keywords:  cell therapy; circadian rhythm; immunology; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3724/abbs.2025203
bioRxiv. 2025 Oct 03. pii: 2025.10.01.679587. [Epub ahead of print]

Collagen-Based Tumor Spheroid Model for Investigating Tumor-Macrophage Interactions through Extracellular Matrix Remodeling.

Luna Zhang, Sanab Abdi, Hannah M Szafraniec, Paolo P Provenzano, Kathryn L Schwertfeger, David K Wood.

  Macrophages in the tumor microenvironment (TME) can constitute up to 50% of tumor mass and play a critical role in cancer cell proliferation, invasion, and metastasis. While their contribution to extracellular matrix (ECM) degradation through matrix metalloproteinases (MMPs) has been explored, the role of other macrophage-derived factors in ECM remodeling and their impacts beyond degradation remain poorly understood. Here, we describe the development of a 3D collagen-based tumor spheroid model to investigate the impact of peripheral blood mononuclear cell (PBMC)-derived macrophages on cancer cell-ECM and cancer cell-macrophage interactions within the TME. We observed that cancer cells stimulated PBMC-derived macrophages into an M2-like phenotype and that tumor spheroid conditioned macrophages (TSCMs) shifted cancer cell populations toward phenotypes with greater invasion distances and reduced circularity, indicative of increased malignancy. Such observations can be explained by macrophage-mediated ECM remodeling. Specifically, we demonstrate that TSCMs secreted a variety of soluble factors that are known to contribute to ECM remodeling, including ECM degradation and fiber realignment. These processes collectively create a tumor-favoring environment by loosening the collagen matrix and aligning fibers that serve as invasion tracks for migrating tumor cells that facilitate cancer cell migration and invasion. This model provides a robust platform to study the interactions between cellular and non-cellular components in the TME and to identify the molecular mechanisms underlying cancer progression. These insights may aid in the development of novel therapeutic strategies targeting macrophage-mediated processes in cancer.

Keywords:  ECM remodeling; Macrophages; Tumor microenvironment; Tumor spheroid model

DOI:  https://doi.org/10.1101/2025.10.01.679587
Mol Biol Cell. 2025 Nov 19. mbcE25050261

Hydrostatic pressure from basal side promotes cancer proliferation, enhances migration and alters cell polarity: a model of the effects of interstitial fluid pressure in tumor microenvironment.

Keisuke Onoi, Aosa Nakamura-Sasada, Shinsaku Tokuda, Mototaka Fukui, Yuki Katayama, Hayato Kawachi, Naoya Nishioka, Masahiro Iwasaku, Toshiyuki Sakai, Tatsuo Furuya, Shunta Ishihara, Satoru Okada, Masayoshi Inoue, Tadaaki Yamada, Koichi Takayama.

The tumor microenvironment contributes to tumorigenesis and tumor progression. Interstitial fluid pressure is elevated in almost all solid malignant tumors, and physical pressure in the tumor microenvironment influences various cancer cell functions, including cell proliferation. However, the direction of the pressure applied to cancer cells has not been considered in previous studies, and the role of physical pressure in the tumor microenvironment in tumor progression remains unclear. Therefore, we investigated the effects of hydrostatic pressure applied to the basal side on lung cancer cells cultured on Transwell filters. Our data show that hydrostatic pressure from the basal side alters various phenotypes of cancer cells, including cell migration, polarity, proliferation, and cell death, all of which are presumed to contribute to tumor progression. These results suggest that physical pressure in the tumor microenvironment provides cancer cells with an advantage in various phenotypes and plays an important role in cancer cell biology. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-05-0261
Int J Cancer. 2025 Nov 19.

C-X-C chemokine receptor CXCR4 mediates diurnal changes in the aggregation and dispersion of CD8+ T cells within the tumor microenvironment.

Akito Tsuruta, Marina Fujimoto, Yasuha Hiraoka, Aoi Taniguchi, Yuki Shiiba, Takuto Inoki, Tomoaki Yamauchi, Yuya Yoshida, Naoya Matsunaga, Shigehiro Ohdo, Satoru Koyanagi.

  Immune checkpoint inhibitors (ICIs) are widely used to treat various types of cancer; however, their effectiveness varies, with some patients exhibiting resistance. Recent studies have shown that the efficacy of ICIs depends on the localization of immune cells, particularly T cells, within the tumor microenvironment (TME). Although the circadian clock is known to regulate immune cell migration into tumors, its role in orchestrating spatially precise intratumoral localization remains unclear. Here, we found that the distribution of CD8+ T cells within the TME varied according to the time of day, accompanied by diurnal expression of C-X-C chemokine receptor type 4 (CXCR4). The amplitude of the Cxcr4 expression rhythm was more pronounced in tumor-infiltrated T cells than in those from the spleen and was associated with time-dependent changes in their migration toward CXCL12-expressing cancer-associated fibroblasts (CAFs). Reanalysis of single-cell RNA-seq data from T cells of lung cancer patients also revealed that upregulation of CXCR4 expression in tumor-infiltrated CD8+ T cells was linked to TGF-β-SMAD signaling. The TGF-β-SMAD signaling-mediated transactivation of Cxcr4 was time-dependently repressed by SMAD7, resulting in diurnal CXCR4 expression. Consequently, administration of a CXCR4 inhibitor during the circadian phase of elevated CXCR4 expression in tumor-infiltrated CD8+ T cells promotes their dispersion throughout tumor tissues, thereby enhancing the efficacy of ICIs. Our findings highlight an unrecognized mechanism underlying diurnal changes in the aggregation and dispersion of CD8+ T cells within tumors, offering a novel approach to enhance the anti-tumor immune effects of ICIs.

Keywords:  circadian rhythm; immune checkpoint inhibitor; tumor microenvironment

DOI:  https://doi.org/10.1002/ijc.70252