bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–02–08
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Targeting Lipid Metabolism in CAFs: A Therapeutic Opportunity in Solid Tumors.
  2. Tumor-associated macrophages in hepatocellular carcinoma: Cellular plasticity and therapy resistance in crosstalk.
  3. TAMs and PD-1 networking in esophageal cancer: literature review.
  4. Post-Treatment Tumor Immune Microenvironment and the Dual Role of Myeloid-Derived Suppressor Cells (MDSCs) in Cancer Progression and Therapeutic Resistance.
  5. Targeting Tumor-Associated Macrophages and Cancer-Associated Fibroblasts to Overcome Therapeutic Resistance in Hepatocellular Carcinoma.
  6. Glutamine metabolism remodels tumor-associated macrophage: mechanistic explorations and new strategies in translational medicine.
  7. Tumor-associated macrophages: Orchestrators of the tumor microenvironment.
  8. Fatty acid metabolic reprogramming in the tumor microenvironment: Unraveling mechanisms and therapeutic prospects.
  9. ITGB1 Regulates Triple-Negative Breast Cancer Development by Modulating the Tumor Microenvironment.
  10. Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.
  11. Writers and Readers of Sialylation in Immunoregulation in Cancer.
  12. The influence of neuro-tumor interactions on tumorigenesis and therapeutic response.
  13. Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles.
  14. Interplay between natural killer cells and ferroptosis: novel insights in tumor immunity and therapeutic potential.
  15. Ectonucleotidases: Possible roles in the tumor microenvironment and influence on tumor progression in breast cancer.
  16. Induced pluripotent stem cell (iPSC)-derived CAR-macrophages: new kids on the block.
  17. SPP1+ Macrophage-POSTN+ Fibroblast-Endothelial Triad Dictates Immunotherapy Response in Bladder Cancer.
  18. [Research progress of Type II immune responses in cancer therapy].
  19. The emerging role of nicotinamide N-methyltransferase in the pathogenesis and treatment of breast cancer.
  20. Immunometabolic editing of the tumor microenvironment: from reprogramming mechanisms to therapeutic vulnerabilities.
  21. Macrophage polarization in hematologic cancers: mechanisms and therapeutic strategies.
  22. Enhancing tumor immunotherapy: the role of ultrasound-mediated micro/nano-bubbles targeting the tumor microenvironment.
  23. Shaping immunotherapy through the tumor microenvironment: Translational perspectives.
  24. Neutrophils in glioblastoma: orchestrators of the tumor microenvironment and immune evasion.
  25. Histone lactylation-derived TET2 enhanced Arg1-mediated MDSC immunosuppression.
  26. Obesity- and tumor-derived signals drive cancer-associated state transitions in breast mesenchymal stromal/stem cells reprogrammed by IL1RA or JAK inhibition.
  1. Transl Res. 2026 Feb 03. pii: S1931-5244(26)00031-9. [Epub ahead of print]
    Targeting Lipid Metabolism in CAFs: A Therapeutic Opportunity in Solid Tumors.
    Qi Ai, Bin Wang, Wei Zhang, Xin-Yun Xu.
      Cancer-associated fibroblasts (CAFs), representing the predominant stromal cell population within the solid tumor microenvironment (TME), are thought to play a significant role in facilitating tumorigenesis and progression. Nonetheless, recent experimental efforts to eradicate CAFs in solid tumors have inadvertently resulted in tumor progression, potentially due to the tumor-suppressive effects exhibited by specific CAF subtypes. Therefore, strategies that selectively target pro-tumorigenic CAFs may yield more favorable outcomes. Emerging evidence indicates that CAFs are instrumental in reprogramming lipid metabolism within TME, fostering a high-fat, immunosuppressive environment. To adapt to the hypoxic and nutrient-limited conditions of TME, cancer cells alter their metabolic processes, which subsequently influences the behavior of CAFs. The variability among CAF populations affects the metabolic pathways of cancer cells and neighboring immune cells. Despite the importance of these interactions, the discussion regarding lipid metabolism crosstalk between CAFs and the TME remains insufficiently explored in the literature. As a result, this study systematically reviews the various origins and heterogeneity of CAFs and closely investigates their roles in lipid metabolism reprogramming within the TME. Additionally, we analyze the metabolic interactions between CAFs and different components of the TME in solid tumors. Ultimately, we discuss potential therapeutic strategies and the challenges of targeting CAF lipid metabolism.
    Keywords:  Cancer-associated fibroblasts; Combined therapy strategy; Immunosuppression; Lipid metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trsl.2026.02.003
  2. J Pharm Anal. 2026 Jan;16(1): 101384
    Tumor-associated macrophages in hepatocellular carcinoma: Cellular plasticity and therapy resistance in crosstalk.
    Tianhao Zhang, Xi Zhao, Tingting Gao, Fang Ma.
      Hepatocellular carcinoma (HCC) is the predominant type of liver cancer. There are different risk factors for HCC including viral infection, liver fibrosis, non-alcoholic fatty liver disease, environmental factors and genomic alterations. The tumor microenvironment (TME) has been proposed as a potent regulator of tumor malignancy comprised of normal and cancerous cells. Macrophages are among the most abundant cells in the TME, known as tumor-associated macrophages (TAMs) that can control proliferation, metastasis, immune reactions and therapy response of tumor cells. In the present review, the function of TAMs in the regulation of HCC progression was evaluated. TAMs are prognostic factors in HCC that increase in TAM infiltration into TME can cause undesirable outcome in patients. Moreover, M2 polarization of macrophages can impair function of other immune cells such as T cells and natural killer (NK) cells to mediate immune evasion. TAMs demonstrate association with other biological events including autophagy and glycolysis. There is mutual interaction between TAMs and exosomes that TAM-mediated exosome secretion regulates HCC progression, while exosomes derived from other cells can also affect TAMs. Inhibition of macrophage recruitment, their depletion and increasing M1 polarization are promising approaches in HCC therapy. The natural products and nanostructures have been also recently introduced for the regulation of macrophages in HCC therapy.
    Keywords:  Drug delivery; Hepatocellular carcinoma; Immunotherapy; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.jpha.2025.101384
  3. ESMO Gastrointest Oncol. 2025 Mar;7 100130
    TAMs and PD-1 networking in esophageal cancer: literature review.
    M Yerolatsite, N Torounidou, A Batistatou, K Katsanos, E Lampri, A-L Amylidi, D Mauri.
       Background: The tumor microenvironment (TME) exerts a profound influence on the progression of cancer cells. Tumor-associated macrophages (TAMs), the most abundant cell population within the TME, exhibit a complex, dual role. On the one hand, TAMs promote inflammation and help eliminate cancer cells; on the other hand, they often adopt an anti-inflammatory role that contributes to the evolution of cancer cells. Furthermore, the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway plays a critical role in both the adaptive and innate immune responses. This study aims to understand the roles of TAMs and the PD-1/PD-L1 signaling network in esophageal cancer.
    Methods: We conducted a systematic review of published data using the Medline (PubMed), Scopus, and Cochrane databases. We included articles that investigated the coexistence of TAMs and the PD-1/PD-L1 pathway in esophageal cancer. Studies that evaluated the clinical prognosis of patients with elevated levels of PD-1-positive TAMs were also incorporated.
    Results: Six articles comprising a total of 822 patients were included in the review. The data indicate a positive correlation between PD-L1 expression and TAMs infiltration. Additionally, patients with high levels of PD-1-positive TAMs tend to have a worse prognosis compared with those with lower levels.
    Conclusions: TAMs play a crucial role in regulating the PD-1/PD-L1 network and the progression of esophageal cancer. Further studies are necessary, however, to clarify the roles of TAMs and the PD-1/PD-L1 network in esophageal cancers.
    Keywords:  PD-1/PD-L1; esophageal cancer; immune checkpoint inhibitors (ICIs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.esmogo.2024.100130
  4. Crit Rev Oncol Hematol. 2026 Jan 29. pii: S1040-8428(26)00035-1. [Epub ahead of print] 105148
    Post-Treatment Tumor Immune Microenvironment and the Dual Role of Myeloid-Derived Suppressor Cells (MDSCs) in Cancer Progression and Therapeutic Resistance.
    Rajdeep Roy, Anusree Haldar, Pritam Kumar Das, Nabendu Biswas.
      The tumor immune microenvironment (TIME) comprises a diverse array of cellular and acellular components that collectively influence immune activation and significantly impact treatment outcomes. Among the several immune cell populations within the TIME, myeloid-derived suppressor cells (MDSCs) play a fundamental role in promoting immunosuppression and driving pathological processes, both before and after therapeutic interventions. Pathological conditions such as surgical stress, administration of pharmacological agents, and exposure to anesthetic compounds have been shown to control the accumulation, development, and mobilization of MDSCs, regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and the secretion of pro-inflammatory cytokines by residual tumor cells. These immunological alterations can initiate a network of complex signaling pathways, ultimately contributing to poor prognosis and, notably, tumor relapse. Emerging evidence from recent preclinical studies underscores the importance of the post-treatment pathological state of the TIME in modulating therapeutic efficacy. Therefore, a comprehensive understanding of the post-treatment TIME landscape is essential for the expansion of precise and effective therapeutic strategies intended at preventing tumor recurrence and metastatic relapse. In this review, we explore the intricate molecular mechanisms and interactions that define the post-treatment TIME, with a specific focus on how pathological states influence MDSC expansion and their dual roles in immunosuppression and anti-tumor responses.
    Keywords:  MDSCs; Pathological state; Tumor immune microenvironment; cancer recurrence; chemoresistance
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105148
  5. Clin Cancer Res. 2026 Feb 04.
    Targeting Tumor-Associated Macrophages and Cancer-Associated Fibroblasts to Overcome Therapeutic Resistance in Hepatocellular Carcinoma.
    Hyo Jung Cho, Minsu Kwon, Judith A Varner.
      Hepatocellular carcinoma (HCC) remains a highly lethal malignancy with limited response to current systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Accumulating evidence highlights the critical role of the tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), in mediating resistance to these treatments. TAMs and CAFs drive immune evasion, extracellular matrix remodeling, angiogenesis, and the promotion of epithelial-mesenchymal transition and cancer stemness. Moreover, their crosstalk via signaling molecules such as osteopontin (SPP1) and transforming growth factor-beta (TGF-β) contributes to the formation of immunosuppressive niches and tumor immune barriers that impair therapeutic efficacy. This review summarizes the mechanisms by which TAMs and CAFs contribute to resistance to ICIs and TKIs and discusses therapeutic strategies under active investigation targeting these stromal components-including inhibition of TGF-β, IL-6, and HGF/MET pathways, TAM reprogramming via PI3Kγ or CD47 blockade, and CAF depletion using FAP-targeted approaches. Targeting the TME holds promise for overcoming therapeutic resistance and improving clinical outcomes in advanced HCC, warranting further evaluation in well-designed clinical trials.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-2944
  6. Front Immunol. 2025 ;16 1715170
    Glutamine metabolism remodels tumor-associated macrophage: mechanistic explorations and new strategies in translational medicine.
    Juya Cui, Xia Yan, Jianbo Song.
      Glutamine metabolism provides energy and raw materials for tumor survival and proliferation. In addition to affecting cancer cells, many studies have investigated the role of glutamine metabolism on the tumor microenvironment in depth. The macrophages, which show high frequently distribution in the majority of solid tumors, are important immune cells in the tumor microenvironment. Tumor-associated macrophage metabolic network remodeling is enormous and complicated. This review links TAM with glutamine metabolism, and combs the network relationship between the unique functional state of macrophages and the key programs of glutamine metabolism in terms of epigenetic modification, signaling pathway transduction, and metabolic checkpoint regulation. In addition, we will summarize the existing glutamine metabolism-targeting drugs and explore the new technologies and strategies for glutamine metabolism to regulate the functional state of TAM.
    Keywords:  glutamine metabolism; glutamine metabolism inhibitors; immune response; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.3389/fimmu.2025.1715170
  7. Am J Physiol Cell Physiol. 2026 Feb 03.
    Tumor-associated macrophages: Orchestrators of the tumor microenvironment.
    John B Echols, Arthur W Meehan, Kathleen A Marotto, Victoria Ordonez, Blake E Hildreth.
      Macrophages are critical cellular mediators within the innate immune system and are the central effectors of chronic inflammation at the cellular level. Here, macrophages regulate the ongoing, simultaneous processes of tissue inflammation, destruction, and repair. They also play an integral role in recruiting key cell types within the inflammatory and wound healing response. Cancer is a chronic inflammatory state and largely considered a wound that does not heal. As in wound healing, where macrophages engulf and/or destroy foreign insults, macrophages have the potential to also eliminate tumor cells. However, it is now well known that these early pro-inflammatory, anti-tumor responses by macrophages are nullified as macrophages repolarize into pro-tumor, anti-inflammatory tumor-associated macrophages (TAMs) in response to tumor cell and microenvironmental-derived factors. After this point, TAMs drive neoplastic progression in multiple distinct ways. This indirect control of tumor progression, where TAMs share great functional overlap with the direct control elicited by neoplastic cells, supports TAMs being central orchestrators and later conductors of the tumor microenvironment (TME) - the focus of our review.
    Keywords:  Tumor-associated macrophage; cancer; macrophage; myeloid; tumor microenvironment
    DOI:  https://doi.org/10.1152/ajpcell.00834.2025
  8. Genes Dis. 2026 May;13(3): 101772
    Fatty acid metabolic reprogramming in the tumor microenvironment: Unraveling mechanisms and therapeutic prospects.
    Wenxin Zhang, Peiwen Wang, Guiqiang Yuan, Fusheng Liu, Guishan Jin, Junwen Zhang.
      Lipid metabolic reprogramming has emerged as a hallmark in cancer research, especially that of fatty acids (FAs). It promotes the effective utilization of the limited nutrients in the tumor microenvironment (TME) by the cells and has considerably been associated with immune escape. Tumor cells exhibit enhanced FA uptake, synthesis, and oxidation for metabolic adaptation, and non-tumor cells also undergo FA metabolic remolding in the TME. Owing to the essential role of FA metabolism in TME, the associated critical enzymes may be targeted for developing novel therapeutic approaches. This review aims to comprehensively summarize the FA metabolic landscapes in various cancers and FA-related molecular changes, FA metabolic reprogramming in different cells in the TME to identify potential targets, and FA-related cell interactions and underlying mechanisms in the TME. The findings of this study may provide insights into exploring the intricate FA metabolism-TME adaptation interplay to uncover potential metabolic targets of therapeutic significance for combinatorial strategies and enhancing immunotherapy.
    Keywords:  Cancer progression; Cell interaction; Fatty acid; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2025.101772
  9. Adv Sci (Weinh). 2026 Feb 03. e13672
    ITGB1 Regulates Triple-Negative Breast Cancer Development by Modulating the Tumor Microenvironment.
    Nuozi Song, Siqi Chen, Lei Wang, Jessica Dang, Xu Cao, Stephanie Singh, Lu Yang, Jinhui Wang, Steven T Rosen, Yingyu Wang, Chun-Wei D Chen, Cheng Zhang, Mingye Feng.
      Tumorigenesis and metastasis are frequently attributed to the intricate interplay between cancer cells and the tumor microenvironment (TME). Comprehending the mechanisms and key regulators of cancer-immune crosstalk in the TME is imperative for developing efficacious immunotherapy. Through a series of in vivo CRISPR screens, we identified tumor-intrinsic ITGB1 as a critical regulator of triple-negative breast cancer (TNBC) development and deciphered its underlying mechanisms. Tumoral ITGB1 facilitated the establishment of pro-tumorigenic TME by orchestrating tumor-associated myeloid populations. Suppressing ITGB1 favored the enrichment of anti-tumorigenic myeloid cells and enhanced infiltration of CD4 and CD8 T cells, culminating in superior antitumor effects. CRISPR scanning pinpointed a previously unrecognized functional domain essential for ITGB1's pro-tumorigenic activity. This domain is distinct from all known ligand-binding sites in ITGB1. An antibody capable of sterically blocking this domain significantly impaired TNBC progression. These findings position tumoral ITGB1 as a promising therapeutic target for reprogramming the TME from a pro- to an anti-tumorigenic state, thereby effectively inhibiting TNBC development. Our study uncovers a novel mechanism of TNBC development and provides a unique therapeutic strategy for targeting ITGB1 in TNBC treatment.
    Keywords:  CRISPR screen; ITGB1; R1 domain; TNBC; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/advs.202513672
  10. Front Immunol. 2025 ;16 1739154
    Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.
    Kunpeng Zhang, Jingjing Liu, Qi Liu, Ningning Zhu, Baodong Ye.
      Macrophages are pivotal regulators of immunity, with intercellular communication being a central mechanism of their function. Among these communications, chemokines act as critical messengers in macrophage-T cell crosstalk. This review systematically elucidates the notable roles of macrophage-derived chemokines in modulating T cell homeostasis, particularly concentrating on their influence on both CD4+ and CD8+ T cell differentiation, proliferation, exhaustion, secretory activity, metabolic reprogramming (involving glycolysis and OXPHOS), chemotaxis, and memory formation. In the tumor microenvironment (TME), the dualistic nature of chemokines was highlighted: tumor-associated macrophages (TAMs) could secrete immunosuppressive factors, such as CCL22 and CCL5, recruiting inhibitory cells and inducing CD8+ T cell exhaustion. In contrast, M1-like macrophages could produce CXCL9 and CXCL10, activating effector CD8+ T cells, thereby enhancing anti-tumor immunity. Finally, the promising therapeutic potential of targeting specific chemokine signaling axes, such as CCL2/CCR2 and CXCL10/CXCR3, was discussed as a strategy to improve the efficacy of cancer immunotherapy.
    Keywords:  T cells; cancer immunotherapy; chemokines; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1739154
  11. J Biol Chem. 2026 Feb 04. pii: S0021-9258(26)00119-5. [Epub ahead of print] 111249
    Writers and Readers of Sialylation in Immunoregulation in Cancer.
    Mathieu Decloquement, Matthew S Macauley.
      Sialic acids are the terminal monosaccharides of the glycocalyx that critically shape cell-cell interactions, and are strongly implicated in regulating immune recognition and tissue homeostasis. In cancer, aberrant sialylation rewires the tumor microenvironment by enhancing ligands of the inhibitory Siglecs, suppressing immune effector functions, and facilitating metastatic dissemination. This review provides a comprehensive synthesis of the dual role of sialyltransferases (the "writers") and Siglecs/Selectins (the "readers") in cancer progression. We examine the structural and functional diversity of these molecules, their dysregulation in malignancy, and their impact on tumor-immune dynamics. Finally, we highlight emerging therapeutic strategies, including sialyltransferase inhibitors, sialidase conjugates, and Siglec-targeted immunotherapies, which collectively position the sialome as a tractable frontier in cancer treatment.
    Keywords:  Cancer immunotherapy; Glycocalyx; Immune evasion; Selectins; Sialylation; Sialyltransferases; Siglecs; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.111249
  12. Exp Hematol Oncol. 2026 Feb 05. 15(1): 18
    The influence of neuro-tumor interactions on tumorigenesis and therapeutic response.
    Xiaokang Wang, Yuanliang Yan, Liugen Li, Tongfei Li, Abhimanyu Thakur, Kui Zhang, Juanni Li, Cheng Zhan, Hailin Tang, Zhijie Xu, Kuan Hu.
      The intricate crosstalk between the nervous system and tumors has emerged as a pivotal determinant of tumorigenesis, progression, and therapeutic response. This review synthesizes current insights into neuro-tumor interactions, highlighting how neuronal networks within the tumor microenvironment (TME) modulate cancer cell proliferation, invasion, and angiogenesis by releasing neurotransmitters, growth factors, etc. The neuro-immune axis, a critical interface linking neural signaling to immune regulation, is explored in depth, elucidating how neuronal-derived molecules influence the phenotype and function of immune cells (e.g., T cells, macrophages, natural killer (NK) cells) to affect anti-tumor immunity. In addition, the review also addresses neurotoxicity associated with tumor progression, particularly tumor-induced neuropathic pain, which arises from treatment-related injury. Finally, the therapeutic potential of targeting neural components in cancer is evaluated, including strategies to disrupt neuro-tumor communication (e.g., neurotransmitter receptor antagonists), modulate neuro-immune crosstalk, and alleviate treatment-related neurotoxicity. Overall, this review underscores the need to integrate neural signaling pathways into cancer biology and therapy, identifying unresolved issues in neuro-oncology and highlighting promising directions for developing neuro-targeted interventions to improve patient outcomes.
    Keywords:  Cancer neuroscience; Nerve-tumor interactions; Neuro-immune axis; Therapeutic implications; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-026-00752-w
  13. Cancer Commun (Lond). 2026 ;46 0008
    Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles.
    Yaxuan Wang, Anqi Lin, Zaoqu Liu, Quan Cheng, Jian Zhang, Peng Luo.
      Cytokines are essential components of the tumor microenvironment (TME) and play crucial roles in tumor initiation and progression. As key mediators of interactions between immune cells and tumor cells within the TME, many cytokines exhibit both protumor and antitumor properties. This complex duality, reminiscent of the balance philosophy pursued by "Onmyoji" in traditional Eastern philosophy, which involves observing and regulating opposing forces to achieve harmony, poses marked challenges in translating cytokine therapies from animal studies to clinical applications. More than 20 key cytokines constituting the TME primarily exert their effects through autocrine and paracrine mechanisms: on one hand, they can activate antitumor immune cells, inhibit tumor growth and metastasis, and induce tumor cell apoptosis to exert antitumor effects; on the other hand, they can also recruit abundant immunosuppressive cells, promote angiogenesis, and facilitate the formation of immunosuppressive microenvironments, thereby preventing natural killer and T cells from exerting their cytotoxic antitumor functions. During acute immune responses triggered by tumor antigens, the body typically stimulates dendritic cell maturation and antigen presentation, leading to antitumor immune responses; however, when acute inflammatory reactions are not promptly resolved, they subsequently transform into chronic inflammation, thereby promoting tumor progression and therapeutic resistance, wherein abundant inflammatory cytokines in the TME play crucial roles in this transition. Currently, the major obstacles to cytokine applications in combination immunotherapy are their poor persistence and uncontrolled toxic side effects, resulting in limited therapeutic efficacy; therefore, reducing toxicity while enhancing efficacy has become a top priority in current cytokine therapy-related research. The effectiveness of cytokines exhibits multifactorial regulation influenced by the unique features of the local TME, cytokine concentration, and the responsiveness profiles of target immune effector cells. This review summarizes current research on cytokines with dual protumor and antitumor effects, with a particular focus on the evolution and regulation of their functions during tumor progression, aiming to provide insights for the future development of personalized immunotherapy strategies targeting cytokines.
    DOI:  https://doi.org/10.34133/cancomm.0008
  14. Cell Commun Signal. 2026 Jan 31.
    Interplay between natural killer cells and ferroptosis: novel insights in tumor immunity and therapeutic potential.
    Jing Sun, Shu Pan, Nan Wang, Xiaoshan Ma, Xige Yang.
      Natural killer (NK) cells are essential components of the innate immune system, executing antitumor functions through direct cytotoxicity and cytokine release. Increasing evidence highlights a bidirectional relationship between NK cell activity and ferroptosis, a regulated form of iron-dependent lipid peroxidation, within the tumor microenvironment (TME). NK cell-secreted interferon-gamma can inhibit tumor antioxidant defenses, such as SLC7A11, thereby sensitizing cancer cells to ferroptotic death. In turn, ferroptotic tumor cells release damage-associated molecular patterns that modulate NK cell recruitment and activation. The TME, characterized by hypoxia, elevated adenosine, and immunosuppressive populations, further regulates this interaction by limiting NK cytotoxicity and promoting tumor resistance to ferroptosis. Preclinical studies indicate that combining ferroptosis inducers with NK cell-based immunotherapies yields synergistic antitumor effects. Additionally, genetically engineered NK cells designed to enhance tumor ferroptotic susceptibility represent a promising strategy to overcome immune evasion. This review summarizes recent discoveries on the NK-ferroptosis axis, delineates the molecular and cellular mechanisms governing their crosstalk in the TME, and explores therapeutic opportunities to leverage this pathway for cancer treatment. Understanding this regulatory network could inform the development of innovative immunometabolic interventions to improve current immunotherapy outcomes.
    Keywords:  Cancer immunotherapy; Ferroptosis; Immunometabolism; Natural killer cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-026-02697-3
  15. Biochim Biophys Acta Gen Subj. 2026 Jan 29. pii: S0304-4165(26)00013-9. [Epub ahead of print]1870(4): 130913
    Ectonucleotidases: Possible roles in the tumor microenvironment and influence on tumor progression in breast cancer.
    Thaís Cristino Rocha-Vieira, José Roberto Meyer-Fernandes.
      Compared with nontumor tissue, the tumor microenvironment has a higher concentration of extracellular ATP. Extracellular ATP is degraded by the cooperative action of CD39 and ecto-5'-nucleotidase (CD73), thus leading to increases in the concentrations of adenosine and phosphate. This cooperative action can convert a proinflammatory environment characterized by a high concentration of ATP into an anti-inflammatory environment characterized by a high concentration of adenosine. In addition to its role in immune suppression, adenosine induces migration, metastasis and angiogenesis in breast cancer. In breast cancer, extracellular Pi plays an important role in tumor progression by increasing metastatic capacity. Studies have demonstrated that ecto-5'-nucleotidases are associated with chemoresistance and immune suppression through adenosine generation. In addition, ecto-5'-nucleotidases play a role in activating the epithelial-mesenchymal transition. Therefore, ectonucleotidase activity may represent a therapeutic target for the treatment of breast cancer.
    Keywords:  Adenosine; Breast cancer; CD39; CD73; Ectonucleotidase; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbagen.2026.130913
  16. Exp Hematol. 2026 Feb 01. pii: S0301-472X(26)00017-2. [Epub ahead of print] 105384
    Induced pluripotent stem cell (iPSC)-derived CAR-macrophages: new kids on the block.
    Fucai Zhu, Zhongfa Chen, Yan Yu, Lanlan Rao, Guifang Lin, Jing Deng, Qiuhua Yu.
      Remarkable outcomes of chimeric antigen receptor (CAR)-T cell therapy in treating hematologic malignancies have inspired parallel efforts to harness the potential of other immune cell types for CAR-based immunotherapy. These efforts aim to overcome the existing limitations of CAR-T cell therapy. In recent years, CAR-macrophages (CAR-MACs) have shown astonishing efficacy in cancer treatment, leading to the approval of several CAR-MAC products for clinical trials. The lack of T-cell receptor (TCR) expression allows them to be used in allogeneic settings and as off-the-shelf products. Within the tumor microenvironment (TME), they can suppress tumor growth via multimodal mechanisms, including CAR-dependent and CAR-independent activities. They can also remodel the TME and prime other immune cells to enhance antitumor responses. Despite these merits, obtaining a sufficient number of MACs from traditional sources is challenging or is subject to regulatory hurdles. This review explores induced pluripotent stem cells (iPSCs) as an emerging source for generating iPSC-derived CAR-MACs (CAR-iMACs). In this regard, we begin with an overview of MACs and their conventional sources, and discuss the advantages of iPSCs over these traditional sources. After that, the technical procedures for generating iPSCs and differentiating them into functional CAR-iMACs are comprehensively discussed. Finally, we explore the preclinical and clinical advances in CAR-iMAC therapy.
    Keywords:  CAR-macrophages; Chimeric antigen receptor (CAR); Immunotherapy; Induced pluripotent stem cells (iPSCs)
    DOI:  https://doi.org/10.1016/j.exphem.2026.105384
  17. FASEB J. 2026 Feb 28. 40(4): e71546
    SPP1+ Macrophage-POSTN+ Fibroblast-Endothelial Triad Dictates Immunotherapy Response in Bladder Cancer.
    Hualin Chen, Yueqiang Peng, Zhigang Ji, Jie Dong.
      Although immunotherapy has shown promise in improving outcomes for bladder cancer (BCa) patients, treatment responses remain highly variable. A comparative examination of the tumor microenvironment (TME) between responders and non-responders may reveal key resistance mechanisms and identify potential therapeutic targets. We integrated spatial transcriptomics, single-cell RNA sequencing, and multiplexed immunofluorescence to characterize spatial structures within the TME that influence response to anti-PD-1 therapy in BCa patients. In non-responders, we observed an accumulation of stem-like malignant epithelial cells with high MYBL2 expression near the tumor boundary. Furthermore, we identified a spatial triad structure-composed of SPP1+ tumor-associated macrophages (TAMs), POSTN+ cancer-associated fibroblasts (CAFs), and endothelial cells-located at the tumor periphery. This structure was associated with T-cell exclusion and reduced efficacy of immune checkpoint blockade. In a preclinical model, inhibiting SPP1 enhanced the response to anti-PD-1 therapy, resulting in reduced CAF infiltration and increased recruitment of cytotoxic T cells. Our study reveals a triad cellular structure mediated by SPP1+ TAMs, POSTN+ CAFs, and endothelial cells that contribute to immunotherapy resistance in BCa. Targeting this structure, particularly through SPP1 blockade, represents a promising strategy to augment the efficacy of immune checkpoint inhibitors.
    Keywords:  POSTN+ fibroblast; SPP1+ macrophage; anti‐PD‐1 therapy; bladder cancer; single cell RNA sequencing; spatial transcriptome; tumor immune barrier
    DOI:  https://doi.org/10.1096/fj.202504456RR
  18. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2026 Feb;42(2): 180-186
    [Research progress of Type II immune responses in cancer therapy].
    Yunfei Dong, Ying Sun, Hongqian Guo, Ke Zeng, Rong Yang.
      Current cancer immunotherapies primarily focus on eliciting Type I immune responses to combat malignancies, yet their efficacy in solid tumors remains suboptimal. The Type II immune response, predominantly mediated by T helper 2 (Th2) cells, regulates immune reactions to infections, allergies, and tissue repair through cytokine secretion. However, emerging evidence reveals its complex and multifaceted role in the tumor microenvironment (TME), where it can either promote tumor progression by facilitating immune evasion and tumor-associated inflammation or exert anti-tumor effects through distinct immunomodulatory mechanisms. On the one hand, interleukin 4 (IL-4) drives M2 macrophage polarization via signal transducer and activator of transcription 6 (STAT6) signaling, synergizing with the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis to amplify immunosuppression. On the other hand, the Th2-associated factors can reprogram anti-tumor immunity in specific therapeutic context, primarily by activating cytotoxic T lymphocytes (CTLs). Recent studies demonstrate that combined immune checkpoint blockade (ICB) therapy not only enhances CD8+ T cell activation and proliferation in tumor-draining lymph nodes by stimulating IL-4 production in follicular helper T (Tfh) cells but also induces IL-5 secretion from CD4+ T cells, triggering an IL-33-eosinophil cascade that promotes intratumoral CD8+ T cell infiltration and effector function. This "pro-tumor vs. anti-tumor" duality underscores the pivotal yet paradoxical role of Type II immunity in tumor immunoregulation. Here, we systematically review the dual functions of Type II immune responses in tumor immunity and their translational potential for next-generation cancer immunotherapy.
  19. Biochem Pharmacol. 2026 Jan 29. pii: S0006-2952(26)00096-1. [Epub ahead of print]247 117765
    The emerging role of nicotinamide N-methyltransferase in the pathogenesis and treatment of breast cancer.
    Shuang-Zhou Bi, Xiang-Li Ni, Wei-Dong Sun, Chen-Ying Zhang, An Liu, Shi-Yan Lai, Jiang-Hua Li.
      Nicotinamide N-methyltransferase (NNMT) plays a critical role in the pathogenesis, progression, and treatment resistance of breast cancer (BC). This enzyme facilitates tumor progression through multiple mechanisms: it regulates NAD+ metabolism, thereby influencing the activity of key enzymes such as sirtuins (SIRTs) and Poly(ADP-ribose) polymerase (PARP), which drives metabolic reprogramming and enhances chemoresistance; it consumes the methyl donor S-adenosylmethionine (SAM), leading to histone hypomethylation and promoting the expression of genes associated with epithelial-mesenchymal transition (EMT) and metastasis; and its metabolite, 1-methylnicotinamide (MNA), acts as a signaling molecule within the tumor microenvironment (TME) to accelerate tumor development by facilitating cell cycle progression and suppressing protective autophagy. NNMT is frequently overexpressed in BC tissues and is correlated with poor prognosis, highlighting its potential as a diagnostic biomarker and therapeutic target. Studies have demonstrated that targeting NNMT effectively inhibits tumor growth and metastasis and may augment the efficacy of immunotherapy. Future research should prioritize the development of potent NNMT inhibitors and further elucidate the role of NNMT in modulating the TME and mediating drug resistance. As a pivotal molecule linking metabolism, epigenetics, and the TME, NNMT offers promising new avenues for BC treatment.
    Keywords:  Breast cancer; Epigenetic regulation; Metabolic reprogramming; Nicotinamide N-methyltransferase; Therapeutic target; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2026.117765
  20. Front Immunol. 2025 ;16 1678446
    Immunometabolic editing of the tumor microenvironment: from reprogramming mechanisms to therapeutic vulnerabilities.
    Yixin Li, Yunmei Zhang, Yan Nie, Xueman Chen.
      Metabolic reprogramming is not only one of the malignant characteristics of tumor cells, but also commonly seen in a variety of immune cells in tumor microenvironment(TME), which massively promotes tumor-body immune interaction. Immunometabolic editing is a dynamic, co-evolutionary process wherein adaptive metabolic reprogramming in the TME, driven by tumor-immune crosstalk during immunoediting, critically shapes anti-tumor immune response and governs immune evasion. Studies of metabolic pathways linked to anti-tumor immune process and discoveries of important therapeutic targets are conducive to the development of targeted immunometabolic intervention to enhance the body's anti-tumor immune response and improve the efficacy of tumor immunotherapies. This review summarizes metabolic characteristics of the TME, highlights immunometabolic editing during cancer evolution, and discusses mechanisms by which tumor immunotherapies modulate tumor immunometabolism to identify potential therapeutic targets.
    Keywords:  immune cells; metabolic reprogramming; stromal cells; tumor cells; tumor immunometabolism; tumor immunotherapy; tumour microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1678446
  21. Blood Res. 2026 Feb 07.
    Macrophage polarization in hematologic cancers: mechanisms and therapeutic strategies.
    Zhi-Gang Chen, Huan Yang, Chao Yang, Yu-Tong Xie, Chen-Mo Li, Tong Xiao, Jun-Hong Wu, Ming-Yang Gao, Cong-Cong Wang, Yu-le Zhao, Jia Liu, Lei Gao.
      Leukemia treatment faces persistent challenges, including chemotherapy resistance and relapse, highlighting macrophage polarization in the tumor microenvironment (TME) as a therapeutic target. Macrophages dynamically shift between antitumor M1 and protumor M2 phenotypes, with M2-polarized tumor-associated macrophages (TAMs) dominating leukemia TMEs. These cells secrete IL-10 and TGF-β, fostering immune evasion, angiogenesis, and leukemia stem cell (LSC) survival. In AML, M2 TAMs correlate with poor prognosis and chemoresistance via CSF-1/IL-10 signaling. Polarization is regulated by transcription factors (STAT6, PPARγ, KLF4), hypoxia, and metabolic reprogramming. Therapeutic strategies focus on: (1) M2 depletion (anti-CD163/CD206 antibodies); (2) Pathway inhibition (CCL2/CCR2 or IL-4/STAT6 blockade); (3) Metabolic modulation (glycolysis/OXPHOS targeting); and (4) Phagocytosis enhancement (CD47-SIRPα blockade, HDAC6 inhibition). Preclinical studies demonstrate CSF-1R inhibitors (e.g., pexidartinib) disrupt LSC-TAM crosstalk, while CAR-M therapy synergizes with phagocytosis-promoting agents. Despite challenges, macrophage-targeted therapies offer transformative potential by remodeling the TME, overcoming resistance, and augmenting immunotherapy. This review outlines mechanistic insights and translational strategies to harness macrophage plasticity for leukemia treatment.
    Keywords:  CAR-M Therapy; CD47-SIRPα Blockade; CSF-1R Inhibitors; Leukemia Stem Cells; Macrophage Polarization; Tumor Microenvironment
    DOI:  https://doi.org/10.1007/s44313-025-00119-w
  22. Int J Pharm. 2026 Jan 30. pii: S0378-5173(26)00083-9. [Epub ahead of print]692 126635
    Enhancing tumor immunotherapy: the role of ultrasound-mediated micro/nano-bubbles targeting the tumor microenvironment.
    Qiaoyu Zhang, Shijin Xu, Qiao Xu, Chenlu Xiao, Xinyi Jiang, Yao Ma, Chaoqi Liu, Yun Zhao, Jun Zhou, Yun Liu.
      Immunotherapy provides a new alternative treatment for patients with malignant tumors, offering them renewed hope. However, many patients experience limited efficacy with immunotherapy, largely due to the tumor microenvironment (TME), which often inhibits the immune response. This reduced efficacy may be attributed to several factors, including hypoxia, immune escape, off-target toxicity, and insufficient drug accumulation. It is widely thought that ultrasound-mediated microbubbles can be used as effective carriers to enhance the effectiveness of immunotherapy by leveraging their active targeting and/or passive targeting of the TME. In this paper, we expound on the targeting effects of ultrasound combined with drug-loaded microbubbles on various components of the TME. Besides, we review how ultrasound-mediated microbubble targeting can refine tumor immunotherapy.
    Keywords:  Immunotherapy; Microbubble; Tumor microenvironment; Ultrasound
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.126635
  23. Crit Rev Oncol Hematol. 2026 Jan 31. pii: S1040-8428(26)00056-9. [Epub ahead of print]220 105169
    Shaping immunotherapy through the tumor microenvironment: Translational perspectives.
    Vansh Vohra, Meenakshi Dhanawat, Rishabh Chalotra, Bharat Bhushan, Garima, Jashan Girdhar, Inamul Hasan Madar, Randhir Singh, Mohammad Fareed.
      The tumour microenvironment (TME) is a simply orchestrator of cancer progression and a principal mediator of resistance to immunotherapy. This review explains the complex immunosuppressive ecosystem of the TME, highlighting mechanisms of immune evasion including the recruitment of regulatory T cells, myeloid-derived suppressor cells, and tumour-associated macrophages; metabolic competition via the Warburg effect and indoleamine 2,3-dioxygenase activity and hypoxia-driven upregulation of immune checkpoints such as PD-L1. We synthesize translational strategies designed to reprogram this hostile niche, moving beyond immune checkpoint inhibitor monotherapy. These approaches encompass metabolic targeting (e.g., MCT1/4, IDO inhibitors), stromal disruption (e.g., CAF inhibition, vascular normalization), and advanced cellular engineering, such as CAR-T cells resistant to exhaustion and cytokine-secreting constructs. We underline the synergy of combination therapies, integrating checkpoint blockade with chemotherapy, radiotherapy, oncolytic viruses, and adenosine pathway antagonists to augment immunogenic cell death and cytotoxic T lymphocyte infiltration. The predictive value of biomarkers including tumour mutational burden, microsatellite instability, and the spatial architecture of tumour-infiltrating lymphocytes is critically appraised. Furthermore, the review explores emerging frontiers such as neoantigen-based vaccines, microbiome modulation, and bispecific antibodies, underscoring their capacity to convert immunologically "cold" tumours into "hot", responsive lesions. By bridging preclinical insights with clinical trial evidence, this review speculates that the precise modulation of the TME is indispensable for unlocking durable, broad-spectrum antitumor immunity and defining the next generation of cancer immunotherapies.
    Keywords:  CAR-T; Cancer immunotherapy; Combination therapies; Immune checkpoint inhibitors; Treg; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105169
  24. Mol Biol Rep. 2026 Feb 03. 53(1): 349
    Neutrophils in glioblastoma: orchestrators of the tumor microenvironment and immune evasion.
    Enes Demir, Elham Rahmanipour, Mohammad Ghorbani, Khushal Gupta, Maryam Zeinali, Michael Karsy.
      
    Keywords:  Glioblastoma; Immunotherapy; Microenvironment; Neutrophils; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1007/s11033-026-11525-3
  25. Front Immunol. 2025 ;16 1677780
    Histone lactylation-derived TET2 enhanced Arg1-mediated MDSC immunosuppression.
    Wenxin Da, Yao Dai, Bo Shen, Yan Zhang, Pengtao Bao, Wei Zhu, Deqiang Wang, Shengjun Wang, Jie Ma.
      In the tumor microenvironment (TME), tumor cells secrete a large amounts of lactate due to the "Warburg effect", which plays a significant role in regulating gene transcription. Recently, the role of lactate in gene transcription has been increasingly understood. Myeloid-derived suppressor cells (MDSCs) are inhibitory cells of bone marrow origin that possess marked abilities to suppress immune cell responses. Within the TME, MDSCs inhibit T cell-mediated specific anti-tumor immunity, as well as non-specific anti-tumor immunity mediated by NK cells and macrophages, by expressing high levels of Arg1, iNOS, and ROS.
    Methods: This study used the Lewis lung carcinoma cell line to establish a lung cancer xenograft model; MDSCs were isolated from the spleens of these mice for subsequent experiments. Protein expression was analyzed by Western blotting, mRNA expression by qRT-PCR, protein-DNA interactions by ChIP-qPCR, and DNA methylation by MSP-qPCR.
    Result: This research shows that histone lactylation enhances the immunosuppressive function of MDSCs. Mechanistically, lactate-induced histone lactylation upregulates TET2, which, using STAT3 as a bridge, modulates ARG1 promoter methylation to upregulate its expression and ultimately enhance the immunosuppressive function of MDSCs.
    Conclusion: This research reveals that the histone lactylation-mediated alteration of TET2 presents a novel therapeutic target for cancer treatment.
    Keywords:  Arg1; MDSCs; STAT3; TET2; lactylation
    DOI:  https://doi.org/10.3389/fimmu.2025.1677780
  26. Exp Hematol Oncol. 2026 Feb 05. 15(1): 16
    Obesity- and tumor-derived signals drive cancer-associated state transitions in breast mesenchymal stromal/stem cells reprogrammed by IL1RA or JAK inhibition.
    Andreas Ritter, Samira Catharina Hoock, Nina-Naomi Kreis, Susanne Roth, Rosario Carolina Torres Colin, Alexandra Friemel, Julia Maria Wildner, Ilona Scherr, Frank Louwen, Christine Solbach, Juping Yuan.
      The tumor microenvironment (TME) in breast cancer is shaped by reciprocal interactions between cancer cells and their surrounding stromal populations. Here, we show that breast adipose tissue-derived stromal/stem cells (bASCs) undergo distinct state transitions in response to tumor cues and systemic metabolic status. Using primary bASCs derived from tumor-adjacent and tumor-distant adipose tissues of breast cancer patients with or without obesity, we identify two functionally distinct, tumor-educated stromal phenotypes: a cytokine-rich inflammatory CAF-like (iCAF) state predominating in lean-adjacent bASCs (ln-aT), and a myofibroblastic CAF-like (myCAF) state emerging in obese-adjacent bASCs (ob-aT). Importantly, transforming growth factor β (TGFβ) is sufficient to induce myCAF-like reprogramming in obesity-primed bASCs, while interleukin 1 (IL1)-Janus kinase (JAK) signaling promotes iCAF features. Re-analysis of single-cell RNA-seq data of breast cancer samples reveals an increased TGFβ expression across stromal and immune cell types in individuals with obesity. Mechanistically, IL1 receptor blockade (anakinra) or JAK inhibition (AZD1480) reverses both iCAF and myCAF phenotypes and functionally suppresses stromal-driven epithelial-mesenchymal transition as well as cancer stemness in breast cancer cells. These findings establish a mechanistic link between obese cues, stromal plasticity, and breast cancer progression, and reveal IL1/JAK signaling as a tractable axis to therapeutically reprogram the breast cancer stroma.
    Keywords:  Adipose tissue-derived mesenchymal stromal/Stem cells; Breast cancer; Cancer stem cells; Cancer-associated fibroblasts; Epithelial-to-mesenchymal transition; IL1/JAK pathway; Obesity; Stromal cell plasticity; TGFβ signaling
    DOI:  https://doi.org/10.1186/s40164-026-00747-7
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