bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–04–12
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Unlocking Cancer Immunity: Deciphering the Role of Tumor-Associated Macrophages in Modulating Immunosuppressive Tumor Microenvironment.
  2. Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
  3. Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.
  4. The metabolic environment within solid tumors drives a complex crosstalk between macrophages and NK cells.
  5. Targeting cholesterol metabolism: A core regulator of tumor-associated macrophage plasticity and immunotherapy response.
  6. Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.
  7. LIFe of the sugar-free party in cancer metabolism.
  8. Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
  9. Reprogramming the tumor microenvironment through vaccine strategies to improve clinical outcomes and guide future innovations.
  10. Cytokine armored CAR T cells for cancer immunotherapy.
  11. Bridging metabolic reprogramming and targeted therapy: the critical role of S-palmitoylation in cancer.
  12. Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer.
  13. Targeting mitochondrial dynamics against cancer.
  14. Harmonizing yin and yang, remodeling the microenvironment: the adjuvant potential of Chinese herbal medicine in tumor immunotherapy.
  15. CCL2: A double-edged sword in neuroblastoma, with a critical role in MYCN-amplified tumors.
  16. Immune cells in keloids: mechanisms and potential treatments.
  17. Leveraging Macrophage Metabolic Reprogramming for Enhanced Anti-Tumor Immunity.
  18. Wnt signaling and the tumor microenvironment: implications for cancer progression and therapeutics.
  19. B7-H3 (CD276) in exosome biogenesis and the tumor microenvironment: a new therapeutic nexus.
  20. Bile acids enrichment fuel tumor aerobic glycolysis and immune evasion via stabilizing FXR-RARα.
  21. Orchestrating Tumor Metastasis: Exosomes as Master Regulators of the Local and Distant Microenvironment.
  1. Cell Biol Int. 2026 Apr;50(4): e70156
    Unlocking Cancer Immunity: Deciphering the Role of Tumor-Associated Macrophages in Modulating Immunosuppressive Tumor Microenvironment.
    Durre Aden, Samreen Zaheer, Sufian Zaheer.
      The tumor microenvironment (TME) significantly influences cancer progression, metastasis, and therapeutic resistance. Among the diverse cellular constituents of the TME, tumor-associated macrophages (TAMs) are critical players that support tumor growth, facilitate angiogenesis, and suppress anti-tumor immune responses. Metabolic reprogramming of TAMs has emerged as a pivotal mechanism driving their immunosuppressive and pro-tumourigenic functions. This extensive review delves into the intricate metabolic pathways involved in TAM reprogramming, the underlying molecular mechanisms, and the impact of these metabolic alterations on the TME. We also explore potential therapeutic strategies targeting TAM metabolism to reprogram the TME and enhance cancer immunotherapy efficacy.
    Keywords:  Cancer Immunity; M1; M2; Macrophages; TAM; Tumor Microenvironment; Tumor‐Associated Macrophages; immune microenvironment
    DOI:  https://doi.org/10.1002/cbin.70156
  2. Cell Mol Immunol. 2026 Apr 07.
    Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
    Yun-Wei Du, Ze-Rong Cai, Xiao-Tong Duan, Xin-Yu Li, Tong Yue, Tian Tian, Jian-Jun Li, Huai-Qiang Ju.
      Given the fundamental biological importance of lipids not only as structural components and energy substrates but also as potent bioactive molecules that govern immune and oncogenic signaling, lipid metabolism reprogramming has emerged as a central driver of tumor progression. Rather than merely fueling tumor growth, this extensive metabolic rewiring profoundly reshapes the tumor microenvironment (TME), establishing complex metabolic crosstalk that actively drives immune evasion. This review examines the current understanding of lipid metabolism reprogramming across different cellular compartments within the TME and its far-reaching implications for cancer immunotherapy. We first delineate how altered lipid metabolism directly fuels tumor cell proliferation, survival, and metastatic potential. We then examine the distinct lipid metabolic patterns in different immune cells, detailing how this reprogramming drives dysfunction in antitumor subsets such as CD8+ T cells and natural killer cells and how it promotes immunosuppressive populations such as tumor-associated macrophages and myeloid-derived suppressor cells. In addition to these immune alterations, we address the metabolic rewiring of stromal cells, particularly cancer-associated fibroblasts. Furthermore, by exploring intricate intercellular crosstalk, we highlight how tumor lipid metabolism promotes immune escape and how lipids from reprogrammed immune and stromal cells, in turn, support tumor growth, thereby reinforcing an immunosuppressive niche. Finally, we highlight emerging therapeutic strategies targeting these pathways and discuss how leveraging multiomics advances can translate lipid insights into cancer immunotherapy.
    Keywords:  Lipid metabolism reprogramming; antitumor immunity; immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.1038/s41423-026-01411-0
  3. Front Immunol. 2026 ;17 1773233
    Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.
    Zikun Hong, Yuming Wu, Wenqi Liu, Dehu Li, Jian Xu.
      Hematologic malignancies (HMs), which originate from hematopoietic or lymphoid tissues, pose a significant therapeutic challenge due to issues such as drug resistance, relapse, and treatment-related toxicity. The tumor microenvironment (TME), especially within the bone marrow niche, is now widely recognized as a critical determinant of disease progression and treatment response. A central mechanism within this specialized niche is the extensive metabolic reprogramming of key stromal and immune cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and bone marrow adipocytes (BMAds). This review systematically elaborates on the alterations in glucose, lipid, and amino acid metabolism within these cellular compartments of the HM-TME. We detail how metabolites such as lactate, fatty acids, and itaconate function not merely as metabolic byproducts but as active signaling molecules that drive critical processes like immune cell polarization, stromal remodeling, and intricate metabolic crosstalk. This comprehensive reprogramming collectively fosters a profoundly immunosuppressive milieu, promotes tumor cell survival and proliferation, and confers resistance to conventional and novel therapies. Furthermore, we explore emerging therapeutic strategies designed to target these metabolic vulnerabilities. These include inhibitors of specific metabolic pathways, modulators of metabolite-driven signaling, and innovative approaches such as nanomedicine and metabolically enhanced immunotherapy. Finally, we outline the current challenges in the field-such as intra-tumoral metabolic heterogeneity and the pressing need for targeted delivery systems-and discuss future perspectives involving advanced technologies like single-cell metabolomics and rational combination strategies. In summary, this synthesis aims to provide a comprehensive and rational foundation for developing novel immunometabolic interventions against HMs, highlighting the therapeutic potential of disrupting the metabolic dialogue within the TME.
    Keywords:  amino acid metabolism; glucose metabolism; hematologic malignancies; lipid metabolism; metabolic reprogramming; tumor microenvironment; tumor-associated cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1773233
  4. Front Immunol. 2026 ;17 1726590
    The metabolic environment within solid tumors drives a complex crosstalk between macrophages and NK cells.
    Didem Cakirsoy Akyoney, Joel Nordin, Samir El Andaloussi, Evren Alici.
      The tumor microenvironment (TME) exerts significant metabolic limitations that influence the activity of invading immune cells. Among them, macrophages and natural killer (NK) cells are essential for coordinating anti-tumor immunity; however, the metabolic conditions of solid tumors have a significant impact on their functional states. Emerging evidence indicates that metabolic competition and nutrition availability regulate the dynamic interactions between these two innate immune populations, eventually influencing immune activation, suppression, and tumor growth. In this review, we discuss how key metabolic factors, including glucose depletion, lipid metabolism, hypoxia, and lactate accumulation, reshape NK cell activity and macrophage polarization in the TME. We emphasize how cytokine signaling and spatial organization within tumors influence NK-macrophage interactions, resulting in either synergistic anti-tumor responses or immunosuppressive networks. Finally, we explore novel therapeutic approaches designed to target metabolic pathways to restore NK cell function and reprogram macrophages toward pro-inflammatory phenotypes. Understanding the metabolic regulation of NK-macrophage interactions could provide new opportunities to improve immunotherapy efficacy in solid tumors.
    Keywords:  anti-tumor immunity; crosstalk; macrophage; metabolic competition; natural killer cells (NK cells); solid tumor; tumor associate macrophages (TAM)
    DOI:  https://doi.org/10.3389/fimmu.2026.1726590
  5. Biochim Biophys Acta Rev Cancer. 2026 Apr 08. pii: S0304-419X(26)00060-0. [Epub ahead of print] 189588
    Targeting cholesterol metabolism: A core regulator of tumor-associated macrophage plasticity and immunotherapy response.
    Danyang Li, Lei Wu, Yongsheng Li.
      Tumor-associated macrophages (TAMs) are one of the main immunosuppressive components in the tumor microenvironment (TME). Growing evidence indicates that their functional state is closely related to metabolic signaling, with cholesterol metabolism dysregulation receiving increasing attention. Abnormal cholesterol metabolism alters membrane lipid composition and signaling pathways, resulting in impaired antigen presentation, upregulation of immune checkpoint molecules, and persistent immunosuppression, thereby facilitating tumor immune evasion and metastasis. The imbalance in cholesterol uptake, esterification, and efflux within TAMs has emerged as a 'metabolic checkpoint' that influences their plasticity between pro-tumoral and anti-tumoral states. In this review, we systematically summarize current research progress on the mechanisms of these processes and discuss how cholesterol metabolism dysregulation reshapes the phenotype of TAMs. We further highlight current therapeutic strategies targeting cholesterol metabolism and the challenges that impede their clinical translation. Finally, we outline emerging advancements in nanomedicine, spatial multi-omics, and artificial intelligence, which may facilitate more precise metabolic reprogramming of TAMs in future immunotherapy.
    Keywords:  Cholesterol metabolism; Metabolic checkpoint; Metabolic reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189588
  6. Front Cell Dev Biol. 2026 ;14 1720480
    Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.
    Jian Yue, Tianyi Pu, Dele He, Yangyong Luo, Simin Ruan, Huahan Li, Jianwei Zhan, Guosen Su, Jianyuan Su, Sheng Chen, Guoxing Huang.
      Immunotherapy resistance remains a major obstacle in treating breast cancer, particularly aggressive subtypes like triple-negative breast cancer (TNBC). This review delineates the pivotal role of the Integrated Stress Response (ISR) as a central metabolic-immune regulator driving this resistance. The ISR is activated in the tumor microenvironment (TME) by diverse stressors-including hypoxia, nutrient scarcity, and ER stress-via four upstream kinases (PERK (PKR-like ER kinase), GCN2, PKR, HRI). These kinases converge to phosphorylate eukaryotic initiation factor 2α (eIF2α), leading to the selective translation and robust activation of the transcription factor ATF4. The ensuing ATF4-driven program fosters an immunosuppressive TME through multifaceted mechanisms: tumor-intrinsic upregulation of PD-L1, secretion of immunosuppressive exosomes, metabolic reprogramming that depletes critical amino acids, and direct impairment of T cell function and antigen presentation. Concurrently, ISR activation in immune cells-such as myeloid-derived suppressor cells (MDSCs) and dendritic cells-further dampens antitumor immunity. Targeting the ISR with small-molecule inhibitors (PERK or GCN2 inhibitors, ISRIB) or repurposed agents (metformin) demonstrates compelling preclinical efficacy in reversing immunosuppression and synergizing with immune checkpoint inhibitors. Biomarker-driven strategies, including ISR gene signatures and p-eIF2α immunohistochemistry, offer promising avenues for patient stratification. Thus, pharmacological targeting of the ISR represents a strategically viable approach to reprogram the immunosuppressive TME and overcome immunotherapy resistance in breast cancer, warranting urgent clinical investigation.
    Keywords:  breast cancer; eIF2α-ATF4 axis; immune checkpoint inhibitors; immunotherapy resistance; integrated stress response (ISR); tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1720480
  7. Trends Endocrinol Metab. 2026 Apr 09. pii: S1043-2760(26)00071-8. [Epub ahead of print]
    LIFe of the sugar-free party in cancer metabolism.
    Khaled Tighanimine, Brendan D Manning.
      Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. demonstrated that glucose withdrawal promotes cancer cell secretion of the cytokine leukemia inhibitory factor (LIF), which exerts protumorigenic effects on the TME.
    Keywords:  LIF; N-glycosylation; PERK; glucose; lung cancer; metastasis
    DOI:  https://doi.org/10.1016/j.tem.2026.03.010
  8. Cancer Discov. 2026 Apr 08.
    Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
    Jian Lin, Chen Sang, Bin Xiang, Xia Shen, Junmei Zhao, Shengshi Xu, Jiaomeng Pan, Youpei Lin, Liangqing Dong, Qianqian Chu, Guoming Shi, Jian Zhou, Jia Fan, Mao Zhang, Qiang Gao.
      Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both Cyclooxygenase/Arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1844
  9. Discov Oncol. 2026 Apr 08.
    Reprogramming the tumor microenvironment through vaccine strategies to improve clinical outcomes and guide future innovations.
    Ali Mohammadi.
      
    Keywords:  Antigen selection; CD39; Cancer vaccines; Clinical trials; Combination immunotherapy; Immunotherapy; Macrophage reprogramming; Personalized oncology; TME reprogramming; Tumor microenvironment; Vaccine delivery platforms
    DOI:  https://doi.org/10.1007/s12672-026-04956-8
  10. Immunol Cell Biol. 2026 Apr 05.
    Cytokine armored CAR T cells for cancer immunotherapy.
    Kevin Sek, Kah Min Yap, Woon Xuan Hong, Phillip K Darcy.
      Cytokine armoring of CAR T cells for enhancing the immunotherapy of cancer. Reprogramming of CAR T-cell phenotypes through (a) IL-158 or (b) IL-9Rα9 engineering. Reprogramming of the tumor microenvironment and recruitment of host antitumor immunity through (c) IL-36γ10 or (d) IL-1211,12 engineering. (e) Tumor-inducible cytokine expression utilizing synthetic NFAT or endogenous NR4A2 promoter systems to restrict systemic expression of potent cytokines for improved safety.
    Keywords:  CAR T cells; cytokine armoring; tumor microenvironment
    DOI:  https://doi.org/10.1111/imcb.70112
  11. Front Cell Dev Biol. 2026 ;14 1802109
    Bridging metabolic reprogramming and targeted therapy: the critical role of S-palmitoylation in cancer.
    Yan Sun, Weiqiang Tang, Ye Xia, Min Xia, Gaohua Liu, Wenjie Zhang, Yajun Chen, Jing Zhong.
      Metabolic reprogramming provides cancer cells with excess fatty acids (FA) to adapt to metabolic stress; however, the precise mechanisms by which these lipid substrates are converted into sustained oncogenic signaling outputs remain incompletely elucidated. This article highlights S-palmitoylation, a reversible post-translational modification (PTM), as a critical molecular bridge linking substrate supply to protein membrane anchoring, stability, and activity. Notably, this interaction forms a malignant positive feedback loop: metabolic reprogramming expands the substrate pool, while aberrant S-palmitoylation conversely stabilizes metabolic enzymes, further exacerbating metabolic disruption. Mechanistically, dysregulated S-palmitoylation not only directly sustains key signaling pathways (RAS/MAPK, PI3K/AKT, and Hippo pathways) to promote stress tolerance but also regulates epigenetic plasticity, synergistically driving tumorigenesis, metastasis, and drug resistance. Beyond intracellular signaling, S-palmitoylation reshapes the tumor microenvironment (TME) by regulating the transport and degradation of immunomodulatory factors, notably promoting immune evasion by inhibiting the lysosomal degradation of programmed death-ligand 1 (PD-L1). This review synthesizes recent advances through three unique organizing pillars: (i) the bidirectional metabolic-palmitoylation feedback loops, (ii) palmitoylation-driven epigenetic plasticity, and (iii) the paradigm shift toward substrate-centric therapeutic designs, aiming to overcome current clinical challenges and enhance the efficacy of immunotherapy.
    Keywords:  S-palmitoylation; epigenetic regulation; immune evasion; metabolic reprogramming; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1802109
  12. Front Immunol. 2026 ;17 1748257
    Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer.
    Siyu He, Xuyan Liu, Qingjie Lv.
      Therapeutic resistance remains the principal cause of mortality in breast cancer. While the tumor microenvironment (TME) is a key contributor, therapies targeting isolated TME components, whether immune, metabolic, or spatial, have largely failed due to compensatory adaptations and ecological resilience. This review synthesizes recent advances to propose a tripartite "Immune-Metabolic-Spatial" axis as the fundamental organizer of a robust resistance niche. We elucidate how immunosuppressive cells, such as TAMs and Tregs, are metabolically sustained by altered nutrient availability like lactate and hypoxia, while spatial constraints, including CAF-deposited ECM and DDR1-mediated collagen alignment, physically impede drug delivery and immune infiltration. Critically, we highlight reciprocal crosstalk where metabolic reprogramming dictates immune cell function, in turn influencing stromal remodeling to create a self-reinforcing resistance loop. Beyond mechanism, we evaluate emerging strategies that concurrently target multiple axes, such as combining immune checkpoint blockade with metabolic inhibitors or stromal disruptors. Finally, we discuss clinical translation through biomarker development and innovative trial designs, framing the tripartite axis as an actionable framework for overcoming therapeutic resistance.
    Keywords:  breast cancer; drug resistance; immune regulation; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1748257
  13. Trends Cell Biol. 2026 Apr 03. pii: S0962-8924(26)00037-1. [Epub ahead of print]
    Targeting mitochondrial dynamics against cancer.
    Yu-Lu Cao, Chao-Pin Yang, Birong Shen, Junjie Hu, Song Gao.
      Although cancer treatment has improved, many patients exhibit limited responses due to the intrinsic heterogeneity and adaptability of tumors, coupled with immunosuppressive conditions in the tumor microenvironment (TME). Mitochondrial dynamics, characterized by continuous fusion and fission, influences cellular processes such as metabolism, cell cycle, cell death, and stemness, thereby profoundly shaping tumor cell evolution and TME plasticity. In this review, we summarize recent advances regarding the roles of mitochondrial dynamics in cancer biology and discuss how it regulates the behavior of both tumor cells and tumor-associated immune cells in the TME. We propose that targeting mitochondrial dynamics represents a dual therapeutic strategy that disrupts core oncogenic programs while potentiating antitumor immunity, offering a promising direction for future cancer treatment.
    Keywords:  TME; immunotherapy; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.006
  14. Front Oncol. 2026 ;16 1806602
    Harmonizing yin and yang, remodeling the microenvironment: the adjuvant potential of Chinese herbal medicine in tumor immunotherapy.
    Xin Gao, Ying Han, Le Yang, Heng Fang, Hui Sun, Ye Sun, Guangli Yan, Ling Kong, Xijun Wang.
      With immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy emerging as the fourth pillar of cancer treatment, modern oncology has entered a new era. However, clinical challenges-including primary/secondary resistance, limited response rates (particularly in "cold tumors"), and potentially severe immune-related adverse events (irAEs)-significantly constrain their applicability and patient benefit. Traditional Chinese medicine (TCM), grounded in its holistic principles of tonifying the body's resistance while eliminating pathogenic factors and syndrome differentiation, demonstrates unique scientific value and translational potential through multi-component, multi-target synergistic actions. It remodels the tumor immune microenvironment (TME), enhances antitumor immune responses, and mitigates immunotherapy-related toxicities. This review systematically synthesizes current evidence elucidating core mechanisms by which TCM formulas, single compounds, and bioactive components enhance efficacy and reduce toxicity. Regarding efficacy enhancement, we focus on TCM's role in reversing T-cell exhaustion, reprogramming tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), inducing immunogenic cell death (ICD), modulating tumor metabolic reprogramming, and optimizing gut microbiota composition to potentiate systemic antitumor immunity. For toxicity reduction, we comprehensively synthesize clinical evidence and pharmacological mechanisms underlying TCM's mitigation of immune-related pneumonitis, colitis, cardiotoxicity, dermatotoxicity, and myelosuppression. This work establishes a robust theoretical foundation and scientific evidence for novel TCM-integrated strategies in cancer immunotherapy, while outlining future directions in the era of precision medicine.
    Keywords:  immune-related adverse events; immunogenic cell death; traditional Chinese medicine; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1806602
  15. Transl Oncol. 2026 Apr 04. pii: S1936-5233(26)00083-5. [Epub ahead of print]67 102746
    CCL2: A double-edged sword in neuroblastoma, with a critical role in MYCN-amplified tumors.
    Léo Jannot, Alexia Gazeu, Nathalie Bendriss-Vermare, Cecile Pochon, Hervé Sartelet.
      Neuroblastoma (NB) is the most common extracranial solid tumor in children, characterized by significant clinical heterogeneity and immune evasion. MYCN oncogene amplification is a major driver of tumor aggressiveness and poor prognosis and is inversely correlated with immune infiltration in the tumor microenvironment (TME). Emerging evidence highlights the pivotal role of the chemokine C-C motif ligand 2 (CCL2) in modulating the immune landscape of NB. CCL2 influences the recruitment of various immune cells, including invariant natural killer T (iNKT) cells, dendritic cells (DCs), monocytes, macrophages, and regulatory T cells (Tregs), thereby shaping either pro- or anti-tumor responses depending on the context. MYCN-amplified tumors display reduced CCL2 expression, resulting in limited immune cell recruitment and the establishment of a "cold" TME with poor immune surveillance. In contrast, non-amplified tumors exhibit higher levels of CCL2, which attracts both anti-tumor immune cells such as DCs and macrophages, as well as pro-tumor populations including Tregs and tumor-associated macrophages (TAMs). These observations underscore the dual and context-dependent role of CCL2 in NB pathogenesis. Therapeutically, targeting the CCL2/CCR2 axis has shown promise in preclinical models, including approaches to enhance CAR-T cell trafficking and reduce TAM-mediated immunosuppression. Overall, CCL2 emerges as a central immunomodulatory molecule in NB, tightly linked to MYCN status and the composition of the TME. Understanding its complex biology is critical for the development of novel immunotherapies aimed at restoring effective anti-tumor immune responses, particularly in high-risk MYCN-amplified NB. Targeting the CCL2 axis represents a promising strategy to improve NB patient outcomes.
    Keywords:  CCL2; Dendritic cells; MYCN amplification; Microenvironment; Neuroblastoma; Opsoclonus myoclonus syndrome
    DOI:  https://doi.org/10.1016/j.tranon.2026.102746
  16. Ann Med. 2026 Dec;58(1): 2655499
    Immune cells in keloids: mechanisms and potential treatments.
    Yuqi Wu, Yuting Huang, Hao Zhang, Chen Dong, Xiaodong Chen.
       BACKGROUND: Keloids are a prevalent pathological fibrotic and proliferative disorder characterized by persistent inflammation and immune dysregulation. In recent years, the critical role of immune cells in keloid development and progression has attracted increasing attention.
    OBJECTIVE: To summarize the immunoregulatory mechanisms and immune dysfunction involved in keloids and to discuss therapeutic strategies targeting these pathways.
    METHODS: Relevant evidence on immune cell populations and immunoregulatory pathways implicated in keloid pathogenesis was reviewed, with emphasis on regulatory T cells, macrophages, dendritic cells, myeloid-derived suppressor cells, CD8+ T cells, and natural killer cells.
    RESULTS: Regulatory immune cells, particularly regulatory T lymphocytes (Tregs), exert important effects on keloid formation. Tregs secrete cytokines such as transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), which suppress inflammation while promoting fibroblast hyperproliferation. M2 macrophages are the predominant macrophage subtype in keloid tissue and contribute to extracellular matrix deposition through the secretion of anti-inflammatory and pro-fibrotic factors. In addition, keloids may exhibit an immune milieu characterized by enrichment of canonical immunoregulatory populations, including regulatory T cells, tolerogenic dendritic cells, and myeloid-derived suppressor cells, together with impaired cytotoxic immune activity involving dysfunctional or exhausted CD8+ T cells and natural killer cells. These alterations collectively support an anti-inflammatory yet pro-fibrotic microenvironment that favors keloid persistence and progression.
    CONCLUSION: Immunoregulatory mechanisms and cytotoxic immune dysfunction are central to keloid pathogenesis. Targeting these pathways may provide a basis for the development of novel immunomodulatory strategies to improve keloid outcomes.
    Keywords:  Immune cells; keloids; pathogenesis
    DOI:  https://doi.org/10.1080/07853890.2026.2655499
  17. Adv Sci (Weinh). 2026 Apr 10. e20903
    Leveraging Macrophage Metabolic Reprogramming for Enhanced Anti-Tumor Immunity.
    Zhiyun Liu, Lingyao Zeng, Xulin Gan, Yilin Zhou, Han Shen, Dan Wu, Xin Shou, Minmin Jiang, Liyun Shi.
      Tumor-associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME), with their metabolic states critically influencing tumor progression or regression. Although reprogramming TAM metabolism is a promising therapeutic avenue, clinical translation remains challenging due to the oversimplified understanding of macrophage plasticity. To bridge these gaps, we first provide an in-depth analysis of the metabolic signatures and functional heterogeneity of TAMs, highlighting key pathways-glycolysis, fatty acid oxidation, and amino acid metabolism-that govern TAM functional diversity. Building on this foundation, we offer a comprehensive overview of current therapeutic strategies targeting critical metabolic regulatory nodes in TAMs and explore future directions for their clinical translation. Ultimately, we propose that precisely modulating the metabolic networks of TAMs can effectively reprogram their immunosuppressive functions, thereby opening new avenues for advancing cancer immunotherapy.
    Keywords:  macrophage polarization; metabolic reprogramming; targeted drug delivery; tumor microenvironment; tumor‐associated macrophages (TAMs)
    DOI:  https://doi.org/10.1002/advs.202520903
  18. Oncogene. 2026 Apr 10.
    Wnt signaling and the tumor microenvironment: implications for cancer progression and therapeutics.
    Ashok Bharathy Mariappan Ragupathi, Chi V Dang, Daniel J Zabransky.
      The Wnt (Wingless/Integrated) signaling pathway is a highly conserved regulator of development, stem cell maintenance, and tissue homeostasis. Its dysregulation is a hallmark of cancer, driving uncontrolled proliferation, epithelial-mesenchymal transition, invasion, and therapy resistance. Increasing evidence shows that Wnt signaling in tumor cells does not operate in isolation but is dynamically shaped by reciprocal interactions with the tumor microenvironment (TME), including fibroblasts, immune and endothelial cells, extracellular matrix, and metabolic stressors. These bidirectional circuits sustain cancer stemness, remodel stromal architecture, and create immunosuppressive and pro-angiogenic conditions that foster tumor growth as well as metastatic dissemination and colonization. In this review, we examine how canonical and non-canonical Wnt pathways intersect with the TME across distinct stages of the metastatic cascade, from local invasion to the establishment of distant niches. We further evaluate therapeutic approaches targeting Wnt signaling and discuss their potential to overcome immune evasion and metastatic progression when combined with immunotherapy or stromal-targeted agents. Finally, we highlight emerging preclinical models, including organoids and tumor-on-a-chip systems, that are advancing our understanding of Wnt-TME crosstalk. Together, these insights position Wnt signaling as a central orchestrator of cancer progression and metastasis and a promising therapeutic target for improving outcomes in advanced cancer.
    DOI:  https://doi.org/10.1038/s41388-026-03731-x
  19. Cell Commun Signal. 2026 Apr 11.
    B7-H3 (CD276) in exosome biogenesis and the tumor microenvironment: a new therapeutic nexus.
    Khaled Omran, Iqra Kousar, Jianrong Lu, Ming Tan.
      Tumor-derived exosomes are powerful mediators of cancer progression, influencing the tumor microenvironment (TME) to promote immune evasion, metastasis, and therapy resistance. B7-H3 (CD276), a member of the B7 immune checkpoint family, is gaining attention as a multifunctional promoter of tumor progression. In addition to its well-known expression on tumor and immune cells, B7-H3 is also enriched in exosomes, where it influences both extracellular vesicle production and signaling. This review examines how B7-H3 impacts exosome biology and contributes to tumor progression. We discuss the mechanisms of exosome biogenesis, including ESCRT-dependent and ESCRT-independent pathways. Emerging evidence indicates that B7-H3 enhances vesicular release, remodels cargo composition, and modulates recipient cell behavior. Mechanistically, B7-H3 activates pathways such as STAT3, PI3K, and lipid metabolism, thereby amplifying oncogenic signaling and promoting a pro-tumor TME. Clinically, B7-H3-enriched exosomes show promise as diagnostic, prognostic, and predictive biomarkers in colorectal, prostate, and non-small cell lung cancers. Additionally, we discuss strategies for therapeutically targeting exosomal B7-H3, including monoclonal and bispecific antibodies, CAR-T cells, and exosome inhibitors, as well as their potential synergy with immunotherapies. Overall, current evidence positions B7-H3 as a crucial link between checkpoint proteins and exosome-mediated cancer progression, offering new avenues for biomarker development and precision oncology.
    Keywords:  B7-H3; Exosomal-B7-H3; Exosome biogenesis; Exosomes; Immunomodulation
    DOI:  https://doi.org/10.1186/s12964-026-02872-6
  20. Front Immunol. 2026 ;17 1750358
    Bile acids enrichment fuel tumor aerobic glycolysis and immune evasion via stabilizing FXR-RARα.
    Hongyu Jiang, Wenyan Xiong, Yingna Feng, Xingjie Li, Jinzhuo Tan, Zongde Zhang.
       Introduction: Fast-growing solid tumors exhibit aerobic glycolysis to meet metabolic demands and evade immune surveillance. While the tumor microenvironment (TME) plays a crucial role in supporting this glycolytic phenotype, the contribution of host metabolites remains incompletely understood.
    Methods: The role of bile acids (BAs) in tumor progression was evaluated using multiple mouse models, including C57BL/6J mice injected with B16 melanoma cells, BALB/c mice inoculated with 4T1 breast cancer cells, and MMTV-PyMT mice with spontaneous tumor development. To assess the impact of BA depletion, subjects were fed a 2% cholestyramine diet compared to a regular diet. The study employed various analytical techniques, including UPLC-MS to evaluate BA profiles, flow cytometry for immune cell analysis, and Seahorse extracellular flux analyzers to measure oxygen consumption and extracellular acidification rates.
    Results: Here, we demonstrate that multiple bile acids (BAs) are significantly enriched in the TMEs of melanoma and breast cancer. Mechanistically, this BA enrichment drives tumor aerobic glycolysis and promotes immune evasion by modulating the interaction between the farnesoid X receptor (FXR) and retinoic acid receptor alpha (RARa). Depletion of BAs in vivo suppressed tumor progression, enhanced T cell infiltration, and alleviated T cell exhaustion, accompanied by transcriptome-wide shifts towardincreased expression of genes involved in oxidative phosphorylation. Furtherinvestigations revealed that BAs activate and stabilize the FXR-RARa complex,thereby upregulating glycolytic pathways and impairing anti-tumor immunity. Conversely, BA depletion reduced FXR/RARa protein levels and disrupted tumorimmune barrier function.
    Discussion: These findings unveil a mechanism by which bile acids promote tumor progression by modulating tumor metabolism and the immune microenvironment through FXR-RARa signaling. Targeting the BA-FXR-RARa axiscould offer promising strategies for cancer therapy and diagnosis.
    Keywords:  aerobic glycolysis; bile acids (BAs); farnesoid X receptor (FXR); immune evasion; retinoic acid receptor alpha (RARα); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1750358
  21. Int J Biol Sci. 2026 ;22(6): 2906-2924
    Orchestrating Tumor Metastasis: Exosomes as Master Regulators of the Local and Distant Microenvironment.
    Yuanke Zhao, Aiyu Liu, Xi Zhang, Anqi Zeng, Linjiang Song.
      Metastasis remains a critical challenge in oncology and constitutes the leading cause of cancer mortality. Recent studies have revealed that exosomes are involved in every step of the cascades of tumor invasion and metastasis. Therefore, it is necessary to further investigate the exosome-mediated intercellular communication network within the tumor microenvironment to elucidate the mechanisms of cancer metastasis. This review summarizes alterations in the tumor microenvironment at primary and metastatic sites during metastasis, encompassing processes such as epithelial-mesenchymal transition (EMT) induction, extracellular matrix (ECM) remodeling, immune suppression, and angiogenesis. In addition, we examine the role of exosomes in mediating tumor drug resistance and explore the clinical translational potential of exosomes in biomarker detection, drug delivery systems, and cancer vaccines.
    Keywords:  cancer metastasis; cancer therapy; exosomes; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.128203
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