bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–01–25
24 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The Progress of Ferroptosis of Immune Cells in the Tumor Microenvironment and Its Impact on Tumorigenesis and Development.
  2. Role of tumor microenvironment in regulator of tumor progression and immunotherapy.
  3. Enzymatic and microenvironmental regulation in adenosine metabolism-mediated immunosuppression.
  4. Decoding the immunoregulatory functions of ALKBH5 in the tumor microenvironment.
  5. Modeling Tumor-Associated Macrophages In Vitro: The Role of Secreted Factors in Tumor Microenvironment Dynamics.
  6. Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification.
  7. Phytonanomedicine: An Assessment of Therapeutic Relevance in Cancer Through Targeting Cancer-Associated Fibroblast in Tumor Microenvironment.
  8. GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
  9. Role of Colorectal Cancer-Derived Exosomes in Modulating Macrophage Phenotypes During Tumor Development.
  10. The role of CCL22 and its histamine-associated modulation in the tumor microenvironment of tongue squamous cell carcinoma.
  11. Midkine (MDK) as a Central Regulator of the Tumor Microenvironment: From Developmental Cytokine to Therapeutic Target.
  12. Role of elevation of glycolysis in tumor-associated macrophages in glioblastoma immune evasion and therapeutic implications.
  13. Heterogeneous neutrophils: Key players in regulating tumor immunity.
  14. Natural killer cell exhaustion in ovarian cancer: from molecular suppression to therapeutic revival.
  15. Peripheral Nerves in Cancer: Regulatory Roles and Therapeutic Strategies.
  16. Emerging role of Saikosaponin A in tumor therapy and tumor microenvironment immunomodulation.
  17. Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy.
  18. A CD36-Targeting Thermosensitive Berberine Nanogel Blocks Tumor Lipid Hijacking and Potentiates Anti-PD-L1 Immunotherapy in Triple-Negative Breast Cancer.
  19. Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer.
  20. A Narrative Review on Photobiomodulation-Guided Immunomodulation: Reprogramming Tumor-Associated Macrophages.
  21. Ferroptosis and its role in immune modulation in breast cancer.
  22. The CDK inhibitor Roscovitine enhances the therapeutic efficacy of anti-PD-1 in non-small cell lung cancer.
  23. The ALKBH1/MYC positive feedback loop regulates TAM polarization and remodels the tumor microenvironment to promote gastric cancer development.
  24. The Trojan Horse Within: Mechanisms of Immune Evasion in Breast Cancer.
  1. Immun Inflamm Dis. 2026 Jan;14(1): e70333
    The Progress of Ferroptosis of Immune Cells in the Tumor Microenvironment and Its Impact on Tumorigenesis and Development.
    Fenfen Zhan, Yanyan Hu, Xiang Jiang, Zejun Fang.
       BACKGROUND: The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides. The interplay between ferroptosis and the tumor immune microenvironment significantly influences the outcome of cancer immunotherapy. The study aims to elucidate the dual effects of ferroptosis on cancer progression and immune responses, particularly in the context of enhancing the efficacy of tumor immunotherapy.
    METHODS: An extensive literature review was conducted using PubMed to identify studies related to ferroptosis and immune cells in the TME, emphasizing translational research outcomes published within the last 5 years.
    RESULTS: The study reviews the literature on the mechanisms of ferroptosis and its interactions with various components of the TME, including immune cells such as CD8+ T cells, dendritic cells, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. It also examines the impact of ferroptosis inducers and inhibitors on these interactions, alongside the potential synergistic effects of combining ferroptosis induction with current immunotherapies. Ferroptosis plays a dual role in the TME by both promoting and inhibiting tumor growth through its effects on immune cell function. Activation of ferroptosis in tumor cells can enhance the immunogenicity of cancer cells, thereby improving the effectiveness of immunotherapies. Conversely, ferroptosis in immune cells can lead to immune cell dysfunction and contribute to immunotherapy resistance. The study identifies several therapeutic strategies that harness the induction of ferroptosis to overcome resistance to immune checkpoint inhibitors and enhance the anti-tumor immune response. Inducing ferroptosis in tumor cells and immunosuppressive cells, while preventing ferroptosis in effector immune cells, emerges as a promising strategy to enhance the efficacy of immunotherapy.
    CONCLUSION: This review highlights the potential of targeting ferroptosis as a sensitization approach to improve cancer treatment outcomes, underscoring the need for further research to fully understand the regulatory mechanisms of ferroptosis in tumor immunity.
    Keywords:  cancer treatment; ferroptosis; immune cells; immunotherapy; therapeutic strategies; tumor immune microenvironment
    DOI:  https://doi.org/10.1002/iid3.70333
  2. Discov Oncol. 2026 Jan 19.
    Role of tumor microenvironment in regulator of tumor progression and immunotherapy.
    Pingping Zhou.
      
    Keywords:  Immune checkpoint; Immunosuppression; Immunotherapy; Tumor microenvironment; Tumor progression
    DOI:  https://doi.org/10.1007/s12672-026-04421-6
  3. Front Immunol. 2025 ;16 1739983
    Enzymatic and microenvironmental regulation in adenosine metabolism-mediated immunosuppression.
    Chuang Li, Lifeng Chen, Zhihao Li, Ling Liang, Benyong Lou.
      Adenosine (ADO), as an endogenous purine nucleoside, can regulate almost all aspects of tissue function. However, its abnormal accumulation in the tumor microenvironment (TME) induces immune tolerance and promotes tumor immune evasion by activating adenosine receptors (ADOR). Regulating ADO metabolism in the TME holds promise for ameliorating ADO-mediated immunosuppression and restoring antitumor immune responses. Extensive research has highlighted the pivotal role of ADO in tumor immune suppression and preclinical development of inhibitors targeting ADOR. However, systematic integration in ADO metabolism of microenvironmental influences, enzyme and protein regulation, and targeted intervention strategies through multiple pathways remain insufficient. This review systematically summarizes the key aspects of targeting ADO-mediated immunosuppression, including the feature of TME, enzymes involved in ADO metabolism (e.g., CD39/CD73/ADK/ADA), and ADOR interventions. Additionally, the necessity of comprehensively regulating ADO metabolism and the immune microenvironment through multi-level coordinated interventions is also explored, as well as the latest combined regulatory strategies. Moreover, the major challenges in current research on ADO metabolic regulation are also critically analyzed and the future research directions are proposed to address the dual challenges of ADO metabolic diversity and TME complexity, aiming to develop more precise and effective immunotherapeutic strategies.
    Keywords:  adenosine metabolism; coordinated intervention; enzymatic regulation; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1739983
  4. Front Immunol. 2025 ;16 1709260
    Decoding the immunoregulatory functions of ALKBH5 in the tumor microenvironment.
    Chunhong Li, Xiulin Jiang, Yixiao Yuan, Qiang Wang.
      N6-methyladenosine (m6A) modification represents the most prevalent internal RNA modification and plays a pivotal role in regulating RNA metabolism and cellular function. As a major m6A demethylase, ALKBH5 not only orchestrates tumor cell proliferation, migration, and metabolic reprogramming but also exerts profound effects on the tumor immune microenvironment (TME). Accumulating evidence has revealed that ALKBH5 regulates immune cell recruitment and function, including CD8+ T cells, Tregs, NK cells, and tumor-associated macrophages, by modulating chemokines, cytokines, and metabolic pathways in an m6A-dependent or independent manner. Moreover, ALKBH5 influences immune checkpoint expression, such as PD-L1, thereby shaping antitumor immune responses and affecting the efficacy of immunotherapy. Upstream regulatory signals, including hypoxia, inflammation, and epigenetic modifications, further fine-tune ALKBH5 expression and activity. Given its dual roles in promoting or suppressing antitumor immunity depending on tumor type and context, ALKBH5 emerges as both a potential biomarker and therapeutic target. Understanding the multifaceted functions of ALKBH5 in tumor immunity provides new insights into precision immunotherapy and may guide the development of novel combination strategies to overcome resistance.
    Keywords:  ALKBH5; cancer immunotherapy; immune checkpoint; m6A demethylase; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1709260
  5. J Vis Exp. 2025 Dec 30.
    Modeling Tumor-Associated Macrophages In Vitro: The Role of Secreted Factors in Tumor Microenvironment Dynamics.
    Denise Risnik, María Catalina Lava, Eugenio Antonio Carrera Silva, Andrea Emilse Errasti.
      Macrophages exhibit remarkable plasticity, enabling them to acquire distinct functional states in response to a variety of environmental cues. In solid tumors, they frequently constitute the most abundant immune cell population within the tumor microenvironment, where they are referred to as tumor-associated macrophages (TAMs). TAMs closely interact with malignant cells, actively promoting tumor progression, angiogenesis, and immune evasion. Tumor cells can reprogram macrophages through direct cell-cell contact and a wide array of secreted factors, shaping their polarization toward pro-tumoral phenotypes. To study these TAM polarization mechanisms in vitro, we propose a method that exposes human monocytes to soluble factors present in tumor cell line-conditioned media. This protocol enables the generation of TAM-like macrophages under controlled conditions, facilitating the analysis of phenotypic and functional changes induced by tumor-derived signals. Our approach offers a reproducible and physiologically relevant model to investigate tumor-macrophage interactions, deepens our understanding of macrophage reprogramming, and supports research into novel therapeutic strategies in cancer immunology and immunotherapy.
    DOI:  https://doi.org/10.3791/69406
  6. Clin Sci (Lond). 2026 Jan 21. pii: CS20256571. [Epub ahead of print]140(2):
    Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification.
    Yangyang Gao, Feifei Guo, Min Li, Naifei Chen, Chao Niu, Jiuwei Cui.
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking advancement in cancer immunotherapy, demonstrating remarkable success in treating hematologic malignancies. However, its application in solid tumors remains challenging. The complex manufacturing process and severe treatmentrelated toxicities further limit its broader clinical application. To address these challenges, researchers are investigating alternative CAR-engineered immune cells, including CAR-NK cells, CAR-γδ T cells, and CARmacrophages (CAR-M), which offer distinct advantages over conventional CAR-T therapy. Notably, CAR-NK and CAR-γδ T cells exhibit HLA-independent cytotoxicity, making them promising 'off-the-shelf' therapeutic options. Meanwhile, CAR-M not only phagocytose tumor cells and present antigens but also remodel the immunosuppressive tumor microenvironment. Despite their potential, these innovative therapies still face several challenges in clinical application. This review systematically summarizes recent advances in CAR-T cells, CAR-NK cells, CAR-γδ T cells, and CAR-M for cancer treatment, providing a comprehensive analysis of their respective strengths, limitations, and future optimization strategies to support the clinical translation of next-generation CAR-based immunotherapies.
    Keywords:  NK cells; chimeric antigen receptor; gamma delta T cells; immunotherapy; macrophages
    DOI:  https://doi.org/10.1042/CS20256571
  7. Phytother Res. 2026 Jan 18.
    Phytonanomedicine: An Assessment of Therapeutic Relevance in Cancer Through Targeting Cancer-Associated Fibroblast in Tumor Microenvironment.
    Sonali Sahoo, Ananya Kashyap, Dillip Kumar Muduly, Sanjeeb Kumar Sahoo.
      Tumors progress within a complex intricate territory consisting of tumorigenic cancer cells with heterogeneous stromal, cellular and non-cellular soluble constituents. The tumor microenvironment (TME) continuously crosstalks with the tumor cells, which helps the tumor cells in achieving different malignant phenotypes and later aids in tumor initiation, progression, and metastasis. Cancer associated fibroblasts (CAFs) constitute a chief component of the TME that is often corroborated with unfavorable disease outcomes, therapy resistance and distant metastasis. CAFs are essential components of TME which facilitate intricate communication between cancer cells, release numerous regulatory factors, thereby aiding tumor growth, synthesize and remodel the extracellular matrix providing drug resistance and regulating immune cell infiltration into TME. Thus, inspecting new therapeutic approaches for targeting CAFs may reverse the current landscape of cancer therapy. Recently, several phytochemicals, such as curcumin, resveratrol, quercetin, silibinin and others, have been studied to demonstrate several regulatory effects on TME. These phytochemicals often target different oncogenic signaling pathways orchestrated within TME components like cancer cells, CAFs, immune cells, cancer stem cells, and endothelial cells crucial for tumor development and progression. Several research findings have demonstrated that different anti-fibrotic phytochemicals in combination with chemotherapeutics have shown better therapeutic efficacy by modulating CAFs in TME. However, despite promising preclinical outcomes, challenges such as poor bioavailability, low solubility, hydrophobicity and obscure target specificity restrict their therapeutic applications in the clinic. There has been acontinually increasing interest to formulate phytonanomedicine, the integration of phytochemicals and nanotechnology using various nanocarriers like liposomes, micelles, and nanoemulsions to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have highlighted the mechanistic pathways through which phytonanomedicine interacts with CAFs, addresses current challenges in clinical translation, and suggests future research directions to optimize the use of natural-product-based nanotherapeutics in anti-CAF strategies for cancer treatment.
    Keywords:  cancer associated fibroblasts; cancer therapeutics; phytochemicals; phytonanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.1002/ptr.70194
  8. Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57
    GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
    Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.
      Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.
    Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004
  9. Carcinogenesis. 2026 Jan 20. pii: bgag003. [Epub ahead of print]
    Role of Colorectal Cancer-Derived Exosomes in Modulating Macrophage Phenotypes During Tumor Development.
    Khandu Wadhonkar, Dhruv Das, Rajani Kant Chittela, Alexander G Obukhov, Mirza S Baig.
      Colorectal cancer (CRC) is one of the deadliest cancer types and is characterized by a complex tumor microenvironment (TME), which includes cancer and immune cells engaging in intricate signaling crosstalk. TME is dependent on the CRC stage and contributes to cancer aggressiveness and therapy resistance. It has been established that tumor-associated immune cells can support cancer progression. However, the underlying mechanisms are not fully elucidated. Here, we provide evidence that communication between CRC and immune cells, particularly tumor-associated macrophages (TAMs), occurs through the release of soluble factors and extracellular vesicles (EVs), such as exosomes. Our study reveals that TAMs initially recognize exosomes as foreign entities, triggering a pro-inflammatory response. Over time, however, the contents of these phagocytosed exosomes reprogram the TAMs into an anti-inflammatory, tumor-supportive phenotype. Our data indicate that such a phenotypic transition in CRC TAMs is primarily triggered by the activation of the NF-kB transcription factor, and that inhibiting NF-kB signaling may significantly decrease the tumor-supportive functions of TAMs in CRC. Thus, pharmacologically slowing the transition of CRC TAMs from pro-inflammatory to tumor-supportive states may be a promising strategy to reduce cancer aggressiveness.
    Keywords:  Colorectal cancer; Exosomes; Macrophages polarization; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1093/carcin/bgag003
  10. Pathol Res Pract. 2026 Jan 19. pii: S0344-0338(26)00024-5. [Epub ahead of print]279 156373
    The role of CCL22 and its histamine-associated modulation in the tumor microenvironment of tongue squamous cell carcinoma.
    Satoshi Kimura, Shohei Shimajiri, Ayumi Nitta, Hiroaki Sato, Hirotsugu Noguchi, Toshiyuki Nakayama.
      Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)-expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor-immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22-CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.
    Keywords:  CCL22; Histamine; Macrophage, tongue SCC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2026.156373
  11. Cancer Lett. 2026 Jan 20. pii: S0304-3835(26)00021-2. [Epub ahead of print] 218258
    Midkine (MDK) as a Central Regulator of the Tumor Microenvironment: From Developmental Cytokine to Therapeutic Target.
    Hareesh B Nair, Ajay Nair, Ya-Guang Liu, Dileep K Vijayan, Ramadevi Subramani, Rajkumar Lakshmanaswamy, Suryavathi Viswanadhapalli, Gangadhara Sareddy, Surinder K Batra, Ratna K Vadlamudi.
      Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK/LTK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and extracellular matrix remodeling, and the establishment of immunosuppressive niches. Across tumor types, MDK is linked to impaired dendritic-cell function, polarization of tumor-associated macrophages, accrual of myeloid-derived suppressor cells and reduced CD8+ T-cell cytotoxic fitness. Finally, we review translational opportunities and challenges, including candidate biomarkers (tumor MDK by IHC/RNA and circulating MDK by ELISA) and rational combination strategies that pair MDK blockade with MAPK-pathway inhibitors or PD-1/PD-L1 immunotherapy. Collectively, these data position MDK as a tractable node connecting tumor-intrinsic signaling with stromal and immune regulation.
    Keywords:  Angiogenesis; Biomarkers; Cancer-associated fibroblasts; Hematologic malignancies; Immune evasion; Immunotherapy; Ligand-receptor interactions; MDK; Single cell transcriptomics; Solid tumors; TME; Tumor immune suppression
    DOI:  https://doi.org/10.1016/j.canlet.2026.218258
  12. PNAS Nexus. 2026 Jan;5(1): pgaf396
    Role of elevation of glycolysis in tumor-associated macrophages in glioblastoma immune evasion and therapeutic implications.
    Jiezhong Chen, Lin Zhu, Tom Lawson, Christopher G Proud, Liming Dai.
      Glioblastoma is a highly aggressive brain cancer with significant mortality, primarily due to CD8+ T cell deficiency, which obstructs effective treatment outcomes. The dysfunction and exhaustion of CD8+ T cells are strongly linked to tumor-associated macrophages (TAMs), which, when exhibiting heightened glycolysis, secrete interleukin-10 and express programmed death ligand 1, both of which suppress CD8+ T cell function. This is under the control of cytokines and growth factors in the glioblastoma tumor microenvironment which activate multiple signaling pathways in TAMs. Moreover, TAMs can increase the aggressiveness of cancer cells by enhancing the activation of oncogenic signaling pathways. Understanding the mechanisms of the roles of glycolysis in TAM development and function as well as the regulation of glycolysis by various signaling pathways has substantial therapeutic implications. In this review, we summarize the most recent progress in TAMs, focusing on glycolysis and examine their interactions with both CD8+ T cells and cancer cells, and their control by signaling pathways. We also discuss in detail the potential therapeutic strategies prompted by new discoveries regarding glycolysis and signaling pathways in TAMs.
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf396
  13. Biochim Biophys Acta Rev Cancer. 2026 Jan 20. pii: S0304-419X(26)00010-7. [Epub ahead of print] 189538
    Heterogeneous neutrophils: Key players in regulating tumor immunity.
    Wenchao Bi, Xue Li, Huajun Zhao, Qiuju Han, Jian Zhang.
      As the most abundant innate immune cells in bone marrow and peripheral blood, neutrophils were once considered functionally homogeneous and exerted inflammatory and anti-infection functions. However, emerging evidence reshapes the perception of neutrophils from passive effectors to dynamic regulators with high plasticity and heterogeneity, especially within the tumor microenvironment (TME). This review summarizes recent advances, particularly driven by single-cell technologies, demonstrating that tumor-associated neutrophils (TANs) represent a continuum of distinct functional states originating from heterogeneous developmental pathways in bone marrow, circulation and spleen. We classified TANs into diverse subsets based on unique molecular signatures and functions, including pro-tumor, inflammatory, interferon-stimulated genes (ISGs)high, and antigen-presenting subsets, and highlighted that TANs profoundly impacting tumor progression through distinct molecular mechanisms. Importantly, we delineate how TANs functionally interact with T cells, NK cells, macrophages and other immune cells, revealing the pivotal role of TANs in reconfiguring immune response networks to modulate tumor progression. Lastly, we discuss emerging therapeutic strategies targeting TAN recruitment, reprogramming, or specific pro-tumor subsets to overcome therapy resistance, aiming to provide insights for future research directions on neutrophils and the development of neutrophil-targeted cancer therapeutic strategies.
    Keywords:  Heterogeneity; Immune modulation; Neutrophil-targeted therapy; Tumor progression regulation; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189538
  14. Front Immunol. 2025 ;16 1709075
    Natural killer cell exhaustion in ovarian cancer: from molecular suppression to therapeutic revival.
    Jun Ning, Lan Yao.
      Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to its late-stage diagnosis and the establishment of an immunosuppressive tumor microenvironment (TME). Natural killer (NK) cells, key effectors of innate immunity, exhibit impaired cytotoxicity within this hostile niche. The dysfunction arises from multiple mechanisms, including suppression by immunosuppressive cytokines (TGF-β, MUC16), shedding of activating ligands (MICA/B, B7-H6, CD155), overexpression of inhibitory immune checkpoints (PD-1, TIGIT), and metabolic reprogramming shaped by glucose and lipid competition. Recent advances in NK cell-based immunotherapies-such as cytokine modulation, adoptive NK transfer, and checkpoint blockade-have demonstrated potential to reverse NK exhaustion and enhance antitumor efficacy. In this review, we systematically dissect the molecular and cellular pathways underlying NK cell suppression in ovarian cancer and evaluate emerging strategies to reinvigorate NK-mediated immunosurveillance.
    Keywords:  NK cell-based immunotherapy; cytokines; immune checkpoints; metabolic reprogramming; natural killer cells; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1709075
  15. MedComm (2020). 2026 Feb;7(2): e70594
    Peripheral Nerves in Cancer: Regulatory Roles and Therapeutic Strategies.
    Yan Fu, Zhi-Shan Ge, Qing-Yue Cao, Zi-Han Li, An Zhang, Hai-Dong Zhu, Gao-Jun Teng.
      Cancer neuroscience has emerged as a transformative frontier in oncology research, focusing on the interplay between cancer cells and the nervous system. Cancer cells establish tumorspecific neural networks within tumor tissues via neurotrophic hijacking. The nervous system regulates tumor initiation, progression, and metastasis either directly by regulating signal transduction in tumor cells or indirectly by modulating the tumor microenvironment (TME). The positive feedback loop between cancer cells and nerves promotes tumor progression. Deciphering the regulatory role of nerves in tumor progression may yield novel anticancer therapeutic options. In this review, the interaction between nerves and cancer cells is described, including how cancer cells hijack and remodel nervous system structure and function, and how neuron-signaling regulates cancer cell growth directly or indirectly through modulating the TME. This evidence of the critical role of nerves in the malignant phenotype of tumors indicates the potential of using neuron-signaling targeting strategies in cancer treatment. By summarizing these findings, this review aims to provide comprehensive insights into the interaction between nerves and cancer cells, paving the way for neuron-signaling-based anticancer therapies.
    Keywords:  cancer; interaction; mechanism; nerve; therapeutic strategies
    DOI:  https://doi.org/10.1002/mco2.70594
  16. Biomed Pharmacother. 2026 Jan 17. pii: S0753-3322(26)00032-6. [Epub ahead of print]195 119000
    Emerging role of Saikosaponin A in tumor therapy and tumor microenvironment immunomodulation.
    Lijie Zhang, Chunjian Wang, Xizhong Zhang, Zhijuan Lin, Feng Chen.
      Saikosaponin A(SSA), a type of saponin compound, is extracted from Bupleurum and is the main active component of this plant. Recent studies have shown that SSA plays important roles in tumor therapy and tumor microenvironment (TME) immunomodulation. Although many new experimental studies on SSA in tumor treatment and immune regulation have been reported, the reviews about its role in tumor treatment and TME are relatively limited. Therefore, this review elaborates the anti-tumor effects of SSA in tumors and their potential mechanisms, including anti-proliferation, induction of apoptosis and ferroptosis, inhibition of metastasis, anti-angiogenesis, inhibition of glycolysis and drug resistance, etc. Moreover, this review reveals the roles of SSA in the TME, points out its regulation on tumor immune cells and cytokines, and clarifies the advantages, limitations and challenges of SSA in tumor treatment. In conclusion, this review summarizes the roles of SSA in tumor treatment and TME regulation, and analyzes the application prospects and challenges of SSA in cancer therapy, which will provide new directions and theoretical basis for clinical cancer treatment.
    Keywords:  Immune therapy; Saikosaponin A; Tumor microenvironment; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biopha.2026.119000
  17. Front Immunol. 2025 ;16 1717541
    Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy.
    Cecilia Profumo, Massimiliano Grassi, Valentina Rigo, Matteo Mascherini, Paola Monti, Giorgia Arcovito, Giorgia Anselmi, Laura Damele, Giorgia Timon, Danila Comandini, Michela Croce.
      Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma characterized by high genomic instability, resulting in high local recurrence rates and limited effective therapeutic options in advanced stages. Recent progress in cancer immunology research has encouraged investigation into the Tumor Microenvironment (TME) of sarcomas, including MFS, to identify immune-related biomarkers of prognostic and therapeutic relevance. Although data remain limited in MFS, existing evidence suggests a heterogeneous immune landscape, including: i) variable expression of immune checkpoint molecules such as Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), ii) presence of tumor-infiltrating lymphocytes, iii) alterations in antigen presentation pathways, and iv) a pronounced angiogenic signature. These findings underscore the potential role of immune biomarkers for patients' clinical stratification and the consequent possibility of developing new immunotherapeutic strategies. This review will focus on the cellular and molecular architecture of immune infiltration, vascular remodeling, and lymphoid neogenesis, assessing their prognostic and predictive value as potential biomarkers. Finally, we will present ongoing clinical trials aimed at modulating the immune-vascular niche to inform innovative therapeutic strategies for this challenging sarcoma subtype.
    Keywords:  biomarkers; immune checkpoint inhibitors; immunotherapy; myxofibrosarcoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1717541
  18. Mol Pharm. 2026 Jan 22.
    A CD36-Targeting Thermosensitive Berberine Nanogel Blocks Tumor Lipid Hijacking and Potentiates Anti-PD-L1 Immunotherapy in Triple-Negative Breast Cancer.
    Wanyu Jin, Shujun Xu, Hongyan Zhang, Yujie Li, Mengna Shi, Ninghui Ma, Xin Zhang, Lujia Zhu, Yang Xiong.
      The limited efficacy of programmed death-ligand-1 (PD-L1) monoclonal antibodies (aPD-L1) in triple-negative breast cancer (TNBC) is largely attributable to the immunosuppressive tumor microenvironment (TME). Notably, the abundance of cancer-associated adipocytes (CAAs) constitutes a distinctive feature of the TNBC microenvironment, contributing significantly to its immunosuppressive nature. CAAs upregulate cluster of differentiation 36 (CD36), a fatty acid translocase on tumor cells, thereby promoting excessive fatty acids (FAs) uptake and lipid droplet (LD) accumulation, which starve immune cells and reinforce immunosuppression through this metabolic adaptation. Berberine (BBR), a bioactive alkaloid derived from Rhizoma coptidis, has previously been shown to ameliorate lipid metabolism disorders through downregulation of CD36 in metabolic diseases such as hepatic steatosis. We therefore hypothesize that BBR inhibits CD36-mediated FAs uptake and reduces LD accumulation in tumor cells, representing a novel mechanism that remains unexplored in the context of TNBC. In this study, we demonstrated that BBR counteracts the tumor-promoting effects of CAAs in 4T1 cells by inhibiting CD36 upregulation and its mediated FAs uptake, thereby reducing CAA-induced LD accumulation and ultimately suppressing tumor cell proliferation. Furthermore, BBR remodeled the TME by enhancing CD8+ T cell recruitment and activity, while reducing immunosuppressive factors. In order to improve the sustained release of BBR at the tumor site and overcome its poor aqueous solubility, we created a thermosensitive hydrogel-based nanoparticle system (BBR-NPs-GEL). This injectable hydrogel demonstrated favorable thermosensitive gelation and shear-thinning behavior, making it suitable for localized administration. It exhibited a gelation temperature of 35.3 ± 0.2 °C and a sustained release profile with 52% of BBR released within 48 h. In 4T1Fluc tumor-bearing mice, BBR-NPs-GEL significantly suppressed tumor growth and remodeled the TME, as evidenced by increased infiltration of CD8+ T cells (+8.49%), activation of dendritic cells (+8.39%), and a shift toward M1-macrophages (+39.9%), accompanied by a reduction in M2-macrophages (-19.13%). Importantly, when combined with aPD-L1 therapy, the treatment elicited synergistic antitumor effects, resulting in enhanced tumor regression. This combination strategy effectively overcame metabolic immunosuppression and reversed immune resistance in TNBC.
    Keywords:  CD36; aPD-L1; berberine nanoparticle thermosensitive hydrogel; lipid uptake; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01378
  19. Biomed Pharmacother. 2026 Jan 17. pii: S0753-3322(25)01161-8. [Epub ahead of print]195 118967
    Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer.
    Yupanun Wutti-In, Piriya Luangwattananun, Nunghathai Sawasdee, Preeyanat Vongchan, Pa-Thai Yenchitsomanus, Aussara Panya.
      The tumor microenvironment (TME) significantly hinders chimeric antigen receptor (CAR) T cell therapy in solid tumors, despite its success in hematological malignancies. This disparity is attributable to immunosuppressive factors, such as program death ligand 1 (PD-L1) upregulation in non-small-cell-lung cancer (NSCLC). This study aims to create and assess anti-FRα-CAR5, a novel anti-folate receptor alpha (FRα) CAR T cell designed to secrete a PD-L1 blocking single chain variable fragment (scFv). Human T lymphocytes were engineered with a lentiviral vector to express anti-FRα-CAR5, which incorporates a fourth-generation CAR backbone (CD28, 4-1BB, CD27, and CD3 zeta) augmented by a secreted anti-PD-L1 scFv derived from atezolizumab. Transfected HEK293T cells were used to evaluate surface expression of anti-FRα-CAR. The secreted anti-PD-L1 scFv was tested for binding ability on lung adenocarcinoma cell lines. Furthermore, the secreted anti-PD-L1 scFv demonstrated over 80 % inhibitory activity against PD-L1 monoclonal antibody. Importantly, anti-FRα-CAR5 T cells enhanced expansion and cytotoxicity against FRα and PD-L1 expressing lung cancer cell lines in vitro compared to an anti-FRα-CAR4 lacking the secreted anti-PD-L1 scFv. This fifth-generation CAR offers a promising strategy to enhance CAR T cell therapy efficacy in PD-L1-mediated immunosuppressive TMEs. These findings suggest that anti-FRα-CAR5 T cells therapy warrants further preclinical validation as a potential treatment strategy for NSCLC patients.
    Keywords:  CAR T cell; Chimeric antigen receptor; FRα; Folate receptor alpha; Immune checkpoint blockade; Non-small cell lung cancer; PD-L1; Secreting anti-PD-L1 scFv
    DOI:  https://doi.org/10.1016/j.biopha.2025.118967
  20. Photobiomodul Photomed Laser Surg. 2026 Jan;44(1): 1-13
    A Narrative Review on Photobiomodulation-Guided Immunomodulation: Reprogramming Tumor-Associated Macrophages.
    Dilpreet Singh.
       AIM: Tumor-associated macrophages (TAMs) constitute a major component of the tumor microenvironment (TME) and are frequently skewed toward an M2-like phenotype that promotes immune suppression, angiogenesis, and tumor progression.
    OBJECTIVES: Reprogramming these macrophages into an M1-like, pro-inflammatory state has emerged as a promising strategy to reinvigorate antitumor immunity and enhance the efficacy of immunotherapeutic interventions. Photobiomodulation (PBM), a non-invasive therapeutic modality utilizing low-intensity red to near-infrared light (600-1100 nm), has shown growing potential in immunomodulation through its effects on mitochondrial bioenergetics, redox signaling, and transcriptional regulation.
    MATERIALS AND METHODS: This review presents a comprehensive analysis of the molecular mechanisms by which PBM influences macrophage polarization, including activation of cytochrome c oxidase, transient increases in reactive oxygen species (ROS) and adenosine triphosphate (ATP), and downstream activation of nuclear factor κB, signal transducer and activator of transcription 1, and hypoxia-inducible factor-1alpha pathways.
    RESULTS: Pre-clinical evidence demonstrates that PBM can effectively reprogram M2-polarized TAMs toward an M1 phenotype, characterized by increased expression of inducible nitric oxide synthase and interleukin (IL)-12 and reduced levels of CD206 and IL-10. When combined with immune checkpoint inhibitors, PBM further enhances CD8+ T cell infiltration and tumor clearance. Nanotechnology-based delivery platforms-such as TAM-targeted upconversion nanoparticles and ROS-sensitive polymeric carriers-have enabled precise, localized PBM activation within tumors, overcoming the limitations of light penetration and systemic exposure.
    CONCLUSION: Collectively, PBM offers a spatiotemporally controlled, drug-free approach to modulate tumor immunity by reeducating TAMs and reshaping the TME. Its integration with existing immunotherapies and nanomedicine holds significant promise for next-generation precision oncology strategies.
    Keywords:  M1/M2 polarization; cancer immunotherapy; immune reprogramming; photobiomodulation; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1177/25785478251406479
  21. Apoptosis. 2026 Jan 19. 31(2): 49
    Ferroptosis and its role in immune modulation in breast cancer.
    Fen Liu, Jiahai H Xiao, Yujuan J Song, Changchun C Zeng.
      Iron-catalyzed lipid peroxidation, a hallmark of the regulated cell death (RCD) known as ferroptosis, has gained prominence in cancer biology, and its application in anticancer treatments is gaining attention. Triggering ferroptosis may curtail the advancement of tumorigenesis, offer opportunities to boost immunotherapy outcomes, and overcome resistance to established oncological interventions. Nevertheless, the function of ferroptosis in immune modulation has not been systematically addressed, particularly in breast carcinoma. This review explores the molecular basis of ferroptosis and discusses the therapeutic implications, particularly in breast carcinoma. Moreover, the complex interrelationship between ferroptosis and immune modulation has been examined, spotlighting how ferroptotic tumor cells can impact simultaneous tumor-suppressive and tumor-promoting immune activities in the breast cancer microenvironment. Furthermore, the involvement of immune cells in regulating ferroptosis has been explored, highlighting the dual interaction dynamics between ferroptosis and immune functions. Additionally, the exploration includes the application of ferroptosis in breast carcinoma immunotherapy, proposing a promising avenue to boost therapeutic efficacy. Ultimately, grasping the bifunctional nature of ferroptosis in immune modulation unveils new perspectives for pioneering breast carcinoma therapies.
    Keywords:  Breast cancer; Ferroptosis; Immunity; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10495-026-02258-6
  22. Front Oncol. 2025 ;15 1745967
    The CDK inhibitor Roscovitine enhances the therapeutic efficacy of anti-PD-1 in non-small cell lung cancer.
    C Marcela Diaz-Montero, Elise G Holvey-Bates, Patricia A Rayman, Yvonne Parker, Daniel J Lindner, George R Stark, Sarmishtha De.
      Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung cancer (NSCLC), yet many patients fail to respond. High PD-L1 expression, often predictive of response, paradoxically correlates with poor prognosis and immune suppression driven by the tumor microenvironment (TME), including myeloid-derived suppressor cells (MDSCs). Roscovitine (Seliciclib), a cyclin-dependent kinase (CDK) inhibitor, downregulates PD-L1 and exhibits immunomodulatory effects, but its potential to enhance ICB efficacy in NSCLC is unknown. Using a syngeneic, immune-competent Lewis lung carcinoma (LLC) mouse model, we evaluated the therapeutic impact of Roscovitine alone or combined with anti-PD-1 therapy. The combination substantially reduced tumor burden, prolonged survival, and induced durable anti-tumor immunity upon tumor re-challenge. Mechanistically, Roscovitine decreased PD-L1 expression on tumor cells and myeloid populations, including circulating and tumor-infiltrating MDSCs, while reducing CCR2+ MDSC frequency in circulation. This was accompanied by increased infiltration of cytotoxic CD8+ T cells and NK cells into the tumor, collectively enhancing anti-tumor immune activity within the TME. These findings demonstrate that Roscovitine potentiates anti-PD-1 therapy by simultaneously suppressing immunosuppressive cell populations and amplifying effector immune responses. The dual modulation of PD-L1 expression and immune cell dynamics provides a strong rationale for the clinical evaluation of Roscovitine in combination with immune checkpoint blockade in NSCLC and potentially other solid tumors.
    Keywords:  PD-L1; circulating immune cells; combination therapy; immune modulation; non-small cell lung cancer; tumor-infiltrating immune cells
    DOI:  https://doi.org/10.3389/fonc.2025.1745967
  23. Int Immunopharmacol. 2026 Jan 21. pii: S1567-5769(26)00064-0. [Epub ahead of print]172 116221
    The ALKBH1/MYC positive feedback loop regulates TAM polarization and remodels the tumor microenvironment to promote gastric cancer development.
    Haiyang Cui, Ang Sheng, Xiaocong Sun, Zhikai Li, Yukun Liu, Linkuan Huangfu, Jiaying Ding, Yingjuan Zheng, Daoke Yang.
      The aim of this study was to investigate the mechanism of action of ALKBH1 in gastric cancer (GC) in regulating tumor-associated macrophage (TAM) polarization and remodeling tumor microenvironment (TME). Through bioinformatics analysis, cellular experiments, molecular biology techniques and in vivo HSC-NPG mouse model experiments, we systematically investigated the expression pattern of ALKBH1 in macrophages and its downstream signaling pathway. Our results showed that ALKBH1 was highly expressed in GC tissues and M2 macrophages, and was closely related to the degree of polarization of M2-type macrophages. Knockdown of ALKBH1 inhibited the polarization of M2 macrophages and strengthened the activity of M1-type macrophages, while enhancing anti-tumor immunity such as CD4+, CD8+ T cells, and NK cells. Further studies showed that ALKBH1 attenuated the m6A modification of USP28 mRNA, and up-regulated USP28 expression. USP28 increased deubiquitination of MYC thereby enhancing the stability of MYC protein, forming an ALKBH1/USP28/MYC positive feedback loop, which promotes M2 polarization and GC development. Knockdown of ALKBH1 rescued the above phenomena and inhibited tumor growth and metastasis in HSC-NPG mice. Our results indicated that ALKBH1 is a key factor regulating TAM polarization and remodeling TME in gastric cancer. Knockdown of ALKBH1 can inhibit gastric cancer progression by suppressing the polarization of M2-type macrophages and enhancing the anti-tumor immune response, which provides an important reference for the development of new therapeutic strategies for GC.
    Keywords:  ALKBH1/USP28/MYC; Gastric cancer; Methylation; TAM polarization; Tumor microenvironment; Ubiquitination
    DOI:  https://doi.org/10.1016/j.intimp.2026.116221
  24. Cancer Heterog Plast. 2025 ;pii: 0001. [Epub ahead of print]3(1):
    The Trojan Horse Within: Mechanisms of Immune Evasion in Breast Cancer.
    Biswajit Das, Charles W Winterbottom, Shaheen S Sikandar.
      Breast cancer (BC) is the most common type of cancer among females, and the number of deaths due to BC has increased over the past few decades. BC is primarily categorized based on the receptor status of BC cells as hormone receptor-positive (HR+), human epidermal growth factor receptor 2-positive (HER2+), and triple-negative BC (TNBC). These subtypes differ significantly in their treatment strategies, prognosis, immunogenic nature, and response to immunotherapy. TNBC is the most aggressive with a poor prognosis, but a subset of TNBCs that express programmed cell death ligand 1, have shown promising responses to immune checkpoint inhibitors. Across BC subtypes, distinct immune cell subsets remain active in the tumor immune microenvironment (TIME) that either inhibit or promote the growth of cancer. In isolation, it is challenging for cancer cells to thrive in presence of the body's immune system, however with the aid of other cells in the TIME, they can work together to evade immune detection by suppressing antigen presentation, modulating immune recognition markers, and recruiting immune-suppressive cells. In this review, we provide an overview of the BC immune evasion mechanisms and discuss aspects of immune evasion in relation to tumor heterogeneity and cellular plasticity. We also highlight successful clinical trials targeting immune-evasion markers and discuss the challenges and potential future directions for solving these problems.
    Keywords:  Breast cancer; Clinical trials; Immune evasion; Tumor heterogeneity; Tumor immune microenvironments
    DOI:  https://doi.org/10.47248/chp2603010001
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒25 at 7:01.