bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–03–08
nineteen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Metabolic causal factor of immune cell function and fate in the tumor microenvironment.
  2. Interactions and communications in hepatocellular carcinoma: Potential targets for chemo/radiosensitization.
  3. Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.
  4. Potentiating dendritic cell immunotherapy by interrupting the Semaphorin 4D-induced immune-suppressive barrier.
  5. Neuroimmunometabolic co-evolution in the tumor micro- and macroenvironment.
  6. The role of nitric oxide in inflammation, tumor microenvironment, and cancer therapy.
  7. Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.
  8. Regulatory T cells in ovarian cancer: Insights into cancer immunotherapy.
  9. The extracellular matrix in inflammation and cancer.
  10. Cancer-associated fibroblasts drive metabolic heterogeneity in colorectal cancer cells: predictions from metabolic modeling.
  11. Correction: FGA modulates immune infiltration and tumor progression via SLC7A11/xCT-mediated disulfidptosis in the tumor microenvironment of lung adenocarcinoma.
  12. The role of IL-6 in tumor immunity and related research progress.
  13. Steroid-induced modulation of the tumor immune microenvironment: Implications for cancer progression and immunotherapy outcomes.
  14. ZG16 represses tumor progression and M2 polarization of tumor-associated macrophages in hepatocellular carcinoma by promoting ubiquitination and degradation of SNX9 via binding to ITCH.
  15. [Research Advances on the Immune Evasion Mechanisms of Disseminated Tumor Cells and Their Roles in Cancer Metastasis].
  16. Targeting cellular source-specific CXCL9 signaling for immunotherapy in oral squamous cell carcinoma.
  17. Research Progress on Tumor-Associated Macrophages and PD-1/PD-L1 Inhibitors in Advanced Colorectal Cancer.
  18. Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models.
  19. CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond.
  1. Bull Cancer. 2026 Mar 02. pii: S0007-4551(26)00105-0. [Epub ahead of print]
    Metabolic causal factor of immune cell function and fate in the tumor microenvironment.
    Fida Noor, Hafeez Noor.
      This study provides an in depth review of understanding the metabolic regulation of immune cells in cancer. Evidence has accumulated in the rapidly developing field of immune metabolism, in which immune cell function and fate are closely linked to their cellular metabolic programs, particularly within the tumor microenvironment. The TME is a metabolically disadvantaged niche characterized by hypoxia, nutrient deprivation, acidosis, and accumulation of immunosuppressive metabolites, all of which result from intense competition for essential resources such as glucose and amino acids. These metabolic constraints profoundly affect the activation, differentiation, and response capacity of the immune cells. This article systematically explores the metabolic reprogramming of immune cells in cancer, with a particular focus on T lymphocytes and myeloid cell populations. We have mapped the metabolic dynamics of T-cells from activation to dysfunction and depletion, elucidating myeloid lineage cells. Finally, we discuss emerging therapeutic strategies that target immune metabolism, including enhancing metabolic adaptation of effector cells, de-inhibiting metabolic checkpoints, reprogramming immunosuppressive cell populations, and combining metabolic interventions with existing immune checkpoint blockade therapies. A deeper understanding of metabolic competition and cooperation within the TME will provide conceptual and transformational evidence for developing more effective and durable cancer immunotherapy. Despite the promise of immunometabolic interventions, translating these strategies into safe and effective clinical therapies remains challenging.
    Keywords:  Cancer immunotherapy; Immune metabolism; Metabolic checkpoints; T-cell exhaustion; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bulcan.2026.01.008
  2. Pathol Res Pract. 2026 Feb 28. pii: S0344-0338(26)00076-2. [Epub ahead of print]282 156425
    Interactions and communications in hepatocellular carcinoma: Potential targets for chemo/radiosensitization.
    Xiu Yan, Xiaoying Dong, Liang Yao, Meihua Guo, Ning Wang.
      Hepatocellular carcinoma (HCC) is known as one of the poor-prognosis malignancies. HCC stroma contains a complex ecosystem. Malignant cells in HCC orchestrate intricate cellular interactions and signaling networks to maintain expansion. The tumor microenvironment (TME) in HCC contains various cells with remarkable plasticity, enabling cancer cells to withstand various therapeutic interventions through multiple resistance mechanisms. Upon exposure to chemotherapy or radiation, HCC cells activate sophisticated DNA damage response (DDR) pathways, cell-cycle checkpoints, and immune-evasion mechanisms. Beyond these mechanisms, HCC employs diverse pro-survival strategies, particularly through the upregulation of anti-apoptotic, angiogenesis, and tyrosine kinases, as well as autophagy modulation. The immunosuppressive landscape of HCC further compounds therapeutic resistance, where cancer-associated fibroblasts (CAFs) serve as key architects in restructuring the stromal compartment. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), neutrophils, and macrophages collectively establish an immunologically "cold" environment that shields tumor cells from both therapeutic agents and immune surveillance. These cellular interactions occur through an elaborate network of cytokines, chemokines, and metabolic intermediates. This review aims to dissect these multifaceted interactions within the HCC microenvironment and explore emerging strategies to disrupt these communication networks, potentially offering novel approaches to enhance the efficacy of conventional chemotherapy and radiation treatment through targeted sensitization.
    Keywords:  Apoptosis, Hepatic Arterial Infusion Chemotherapy (HAIC), Immune Checkpoint Inhibitors (ICIs); Chemotherapy; Hepatocellular carcinoma (HCC); Radiotherapy; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.prp.2026.156425
  3. Cell Rep Med. 2026 Feb 27. pii: S2666-3791(26)00049-2. [Epub ahead of print] 102632
    Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.
    Aleksandra Georgievski, Noémie Blanc, Mélanie Bruchard, Cassandre Pignol, Pierre-Simon Bellaye, Carmen Garrido, Ronan Quéré.
      We develop valrubicin-loaded immunoliposomes (Val-ILs), a nanoparticle-based therapy designed to target immunosuppressive cells that promote immune evasion in cancer. In vivo screening following intravenous administration in mice identifies nine relevant surface targets, including known immunoregulatory markers (LAG-3 and VEGFR2) and not-well-characterized candidates (CD11b, CD64, TIM1, CD200R3, CD204, CD49b, and SIGLEC-F). Within the tumor microenvironment, Val-ILs treatment broadly reduces the expression of these antigens on immunosuppressive populations, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and T helper 17 cells, as well as on innate anti-tumor cells such as tumor-associated natural killer cells and tumor-infiltrating dendritic cells. Across four murine cancer models, two responsive (T and B lymphomas) and two resistant (orthotopic breast and lung cancers), Val-ILs decorated with antibodies against the nine targets significantly enhance anti-PD-1 efficacy. This combination boosts the presence of CD4+ and CD8+ tumor-infiltrating lymphocytes, reprograms tumor-associated macrophages toward an M1-like phenotype, and improves tumor control and metastasis reduction.
    Keywords:  enhance anti-tumor immunity in resistant cancer models; immunosuppressive cells; murine cancer models; nanoparticle-based therapy; reduced metastasis; tumor regression; valrubicin-loaded immunoliposomes
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102632
  4. Cell Rep. 2026 Mar 04. pii: S2211-1247(26)00128-2. [Epub ahead of print]45(3): 117050
    Potentiating dendritic cell immunotherapy by interrupting the Semaphorin 4D-induced immune-suppressive barrier.
    Saurabh K Garg, Colin Snyder, Ganesan Ramamoorthi, Krithika N Kodumudi, Elizabeth E Evans, Vincent Lok, Holm Bussler, Jonathan V Nguyen, Jiqiang Yao, Amrita Basu, Namrata Gautam, Julio A Vazquez Martinez, Darwin C Chang, Amy L Aldrich, Doris Wiener, Paulo C Rodriguez, Maurice Zauderer, Gary K Koski, Brian J Czerniecki.
      Immune suppression within the tumor microenvironment (TME) remains a significant barrier to effective cancer immunotherapy, including dendritic cell (DC)-based approaches. We address this by targeting Semaphorin 4D (SEMA4D), a pro-tumorigenic mediator expressed by leading-edge tumor cells and host immune cells, particularly in HER2-positive (HER2pos) breast cancer (BC). Antibody blockade of SEMA4D enhances the efficacy of adoptively transferred tumor-specific conventional type 1 DCs (cDC1s) across multiple HER2pos BC models. Tumor-cell-specific ablation of SEMA4D activity amplifies cDC1-driven anti-tumor immunity, highlighting its role in immune evasion. SEMA4D blockade synergizes with cDC1s to increase CD4+ Th1 and other effector cell infiltration into the TME, along with reciprocal elimination of myeloid-derived suppressor cells, fostering robust systemic immune responses that eradicated both local and distant tumors. Given its favorable safety profile, this strategy represents a promising immunotherapy for malignancies, including HER2pos BC that express high levels of SEMA4D in both tumor and stromal compartments.
    Keywords:  CP: cancer; CP: immunology; Semaphorin 4D; breast cancer; dendritic cells; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117050
  5. Cell Metab. 2026 Feb 27. pii: S1550-4131(26)00044-6. [Epub ahead of print]
    Neuroimmunometabolic co-evolution in the tumor micro- and macroenvironment.
    Yu Zhang, Weijie Zhuang, Haodong Zhu, Fansheng Meng, Mingtao Chen, Yibo Guo, Jia Fan, Yunfan Sun, Tong Ji.
      The nervous system integrates immune, endocrine, and circulatory systems to coordinate complex physiological responses. It influences tumor progression and treatment resistance through interactions with cancer cells and immune cells and by regulating metabolic processes within both the tumor microenvironment (TME) and tumor macroenvironment (TMaE). This review provides a comprehensive overview of the neuroimmunometabolic co-evolution within the TME and TMaE. At the TME scale, we discuss the role of the peripheral nervous system (PNS), including sympathetic, parasympathetic, and sensory neurons, in regulating metabolic processes and immune cell functions. At the TMaE scale, we highlight how cancer cells exploit brain-body interactions to reprogram systemic metabolism and immune responses, creating conditions that favor tumor progression. Additionally, we describe how the PNS serves as a conduit for long-range communication between tumors and distant organs. Finally, we identify key knowledge gaps, propose strategies to address current limitations, and discuss clinically actionable neuroimmune and neurometabolic therapies.
    Keywords:  brain-body interactions; cancer immunology; cancer metabolism; cancer neuroscience; neuroimmune interactions; neurometabolic interactions; tumor macroenvironment; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.001
  6. Nitric Oxide. 2026 Feb 28. pii: S1089-8603(26)00020-0. [Epub ahead of print]162 25-34
    The role of nitric oxide in inflammation, tumor microenvironment, and cancer therapy.
    Akhil Nair, Harishkumar Madhyastha, B C Revanasiddappa, Vasudev Pai, Dileep Kumar, M K Neenu, Pavithra Pradeep Prabhu.
      Nitric oxide (NO) is a widespread signaling molecule which has far-reaching effects in cellular physiology and pathophysiology, especially in cancer biology. Its actions are concentration-dependent where low concentrations facilitate tumor development and high concentrations cause cytotoxicity. NO alters several cancer hallmarks, affecting the initiation, progression, immune evasion, and therapeutic responses of tumors via cGMP-dependent and -independent pathways. Various cell types in the tumor microenvironment (TME) produce NO in a concentration gradient creating a strong concentration gradient that forms the immune landscape. NO mediates immunosuppression through the regulation of tumor-associated macrophage, myeloid-derived suppressor cell, T cells, and natural killer cells. It also controls angiogenesis and normalization of the vasculature via the VEGF-NO axis. Moreover, NO effects epithelial-mesenchymal transition and metastasis concentration-dependently. Notably, NO exists in a complex interaction with gasotransmitters, and it interacts with hydrogen sulfide and carbon monoxide in crosstalk to control cancer biology. Therapeutic interventions that focus on NO e.g., NO donors, iNOS-inhibitors and nanodelivery systems have been promising in preclinical practice. Nevertheless, clinical translation is complicated by the fact that the concentrations of intratumoral NO have to be tightly controlled, safety issues exist, and there are not many biomarkers of patient stratification. Integration of NO-based therapies with immunotherapy and precision medicine approaches holds promise for enhancing treatment outcomes. Continued research spanning chemical, biological, and clinical domains is crucial for unlocking the full therapeutic potential of NO in cancer.
    Keywords:  Cancer; Inflammation; Nitric oxide; Peroxynitrite; Reactive nitrogen species; Tumor microenvironment; iNOS
    DOI:  https://doi.org/10.1016/j.niox.2026.02.005
  7. Mol Immunol. 2026 Mar 05. pii: S0161-5890(26)00041-6. [Epub ahead of print]192 45-56
    Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.
    Fei Lan, Jin Song, Xinfeng Chen, Yi Zhang.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of relapsed or refractory hematological malignancies, particularly acute B-cell lymphoblastic leukemia (B-ALL), B-cell lymphoma (BCL), and multiple myeloma (MM). However, resistance in hematological malignancies and limited immune responses in solid tumors remain major challenges for CAR-T cell therapy. Tumor antigen loss or modulation, dysregulated apoptotic signaling, CAR-T cell-intrinsic dysfunction, and immunosuppressive components within the tumor microenvironment (TME) significantly compromise therapeutic outcomes. Therefore, understanding the mechanisms that mediate resistance to CAR-T cell therapy and exploring strategies to overcome therapeutic failure are crucial for optimizing clinical results. This review systematically elucidates the mechanisms underlying resistance to CAR-T cell therapy and discusses potential countermeasures, including dual-targeted approaches, innovative CAR engineering strategies, TME reprogramming, and combination immunotherapies.
    Keywords:  CAR-T cell; Immunotherapy; Resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molimm.2026.02.011
  8. Crit Rev Oncol Hematol. 2026 Feb 28. pii: S1040-8428(26)00124-1. [Epub ahead of print]221 105237
    Regulatory T cells in ovarian cancer: Insights into cancer immunotherapy.
    Yueer Chang, Jianyu Yu, Zhixin Qiu, Juan Zhang, Zheng Yang, Jinan He, Na Li, Han Wang.
      Ovarian cancer (OC) is a formidable malignancy characterized by a notably diminished five-year survival rate. Current evidence demonstrates that OC orchestrates the establishment of an immunosuppressive tumor microenvironment (TME), thereby affording tumor cells a favorable milieu to evade immune surveillance and resist therapeutic interventions. Central to this immunosuppressive landscape are regulatory T cells (Tregs), which infiltrate both tumor sites and circulation. Within the TME, OC cells interact with these Tregs and other immunosuppressive networks to promote tumorigenesis, progression, and metastasis. Recent investigations have predominantly concentrated on elucidating the activation mechanisms and diverse functional states of Tregs across distinct human pathologies. Nevertheless, further study is needed to revolve around the substantial contributions of tumor-infiltrating Tregs in the context of OC. In this review, we provide an overview of present advances in Tregs' heterogeneity and their multifaceted functions within the TME, encompassing immunologic tolerance, immune evasion, metabolic reprogramming, and microenvironmental remodeling. By integrating TME and therapy perspectives on Tregs in OC, this review bridges existing gaps in the literature and aims to offer emerging insights for precise immunotherapeutic strategies specifically for OC.
    Keywords:  Immune evasion; Immunologic tolerance; Immunotherapy; Ovarian cancer; Regulatory T cell; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105237
  9. Mol Biomed. 2026 Mar 06. pii: 21. [Epub ahead of print]7(1):
    The extracellular matrix in inflammation and cancer.
    Wanting Zhang, Yuhang Xiang, Chen Lu, Fei Wang, He Ren, Hao Wu, Meisi Yan.
      The extracellular matrix (ECM) forms a dynamic structure around cells, providing environmental cues, mechanical support, and tissue protection. It is composed of fibrous proteins, glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. The molecular, physical, and mechanical properties of the ECM regulate the motility, survival, and function of immune cells. In most cancers, inflammatory cytokines and proteases-particularly matrix metalloproteinases(MMPs)-released within the immune-infiltrated inflammatory microenvironment can remodel the ECM. Cytokines such as tumor necrosis factor-α (TNF), interleukin, and transforming growth factor-beta (TGF-β) modulate the expression of various ECM molecules and promote host cell differentiation, thereby shaping a stroma conducive to tumor survival and metastasis. When ECM components become dysregulated, they act as ligands interacting with immune cell receptors, suppressing the function of specific immune cell subsets in the tumor microenvironment (TME), and activating downstream intracellular signaling pathways that are exploited by cancer cells to facilitate progression. This review systematically outlines key ECM constituents, molecular mediators of ECM remodeling, and their role in regulating immune cell behavior, including T cell exhaustion and macrophage polarization. It also elucidates the direct interactions between ECM and immune cells within inflammatory settings. Furthermore, we explore therapeutic strategies targeting ECM-mediated immunosuppression in solid tumors. This study highlights promising approaches to enhance the efficacy of cancer immunotherapy.
    Keywords:  Extracellular matrix; Extracellular matrix remodeling; Immune response; Inflammation; Therapeutic strategies
    DOI:  https://doi.org/10.1186/s43556-026-00415-6
  10. NPJ Syst Biol Appl. 2026 Mar 04.
    Cancer-associated fibroblasts drive metabolic heterogeneity in colorectal cancer cells: predictions from metabolic modeling.
    Elizabeth Elton, Niki Tavakoli, Handan Cetin, Stacey D Finley.
      KRAS-mutant colorectal cancer (CRC) undergoes metabolic reprogramming that promotes tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play a pivotal role in modulating these metabolic adaptations in CRC. This study applies flux sampling combined with representation learning and hierarchical clustering to a computational model of central carbon metabolism to understand how CAFs influence KRAS-mutant CRC metabolic reprogramming following targeted enzyme knockdowns. Focusing on 12 key enzymes involved in glycolysis and the pentose phosphate pathway, knockdowns were simulated under normal CRC media and CAF-conditioned media (CCM) conditions. Analysis revealed CCM induces greater metabolic heterogeneity, with knockdown models exhibiting more variable and distinct metabolic states compared to those cultured in normal CRC media, indicating CAF-derived factors diversify the metabolic responses of CRC cells to enzyme perturbations. Pathway-level flux analysis demonstrated media-specific shifts in central carbon metabolism. Predicted biomass flux showed enzyme knockdowns reduced growth across both conditions, but CCM models indicated a protective effect against perturbation. Overall, simulations illustrated CCM enhances the metabolic adaptability of KRAS-mutant CRC cells to perturbations, emphasizing the importance of including TME components in metabolic modeling and therapeutic development and suggesting that targeting tumor-CAF metabolic interactions may improve treatment strategies.
    DOI:  https://doi.org/10.1038/s41540-026-00673-8
  11. Front Immunol. 2026 ;17 1789896
    Correction: FGA modulates immune infiltration and tumor progression via SLC7A11/xCT-mediated disulfidptosis in the tumor microenvironment of lung adenocarcinoma.
    Gen Li, Qiuping Li, Sheng Yang, Dongmei Guo, Yanling Tao, Yan Jia.
      [This corrects the article DOI: 10.3389/fimmu.2025.1595900.].
    Keywords:  disulfidptosis; immune infiltration; lung adenocarcinoma; non-small-cell lung cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1789896
  12. Cell Signal. 2026 Mar 04. pii: S0898-6568(26)00110-5. [Epub ahead of print] 112460
    The role of IL-6 in tumor immunity and related research progress.
    Ping Huang, Rong Yin, Weina Xu, Shenggeng Wang, Hongmei Yong, Tian Yang.
      IL-6 is the primary mediator of inflammation. It can be secreted by immune cells, tumor cells, and stromal cells, which is highly expressed in tissues from tumors. Through its downstream signaling pathway, IL-6 regulates nearly every aspect of the tumor to encourage its occurrence and progression. Additionally, it impacts immunosuppressive molecule expression, impacts the tumor microenvironment's immunological and non-immune cell counts and composition, and promotes the growth of a tumor microenvironment that suppresses the immune system. Immunotherapy is a commonly used treatment method nowadays. However, in most patients with cancer, immunotherapy often exhibits low response rates and drug resistance. The secret to increasing the efficacy of tumor immunotherapy is to overcome the tumor microenvironment's immunosuppressive state. In recent years, researchers have developed a number of drugs that target the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling cascade, and related studies on combining immune checkpoint inhibitors with it, providing the new direction for immunotherapy in tumor patients. This article reviews the specific mechanism of IL-6 on tumor immunity and summarizes the latest research findings on blocking IL-6 or its downstream-related signaling pathways.
    Keywords:  IL-6; Immune cells; Immune checkpoint inhibitors; Small molecule inhibitors; Tumor immunity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112460
  13. J Steroid Biochem Mol Biol. 2026 Mar 01. pii: S0960-0760(26)00044-0. [Epub ahead of print]259 106978
    Steroid-induced modulation of the tumor immune microenvironment: Implications for cancer progression and immunotherapy outcomes.
    Kanimozhi Kaliyamoorthi.
      Glucocorticoids (GCs) remain indispensable in oncology due to their strong anti-inflammatory, anti-oedema, and immunosuppressive effects, which are crucial for controlling cancer symptoms and treatment-related toxicities. However, the expanding use of immunotherapies, particularly immune checkpoint blockade and CAR-T cell approaches, has highlighted the paradoxical influence of steroids on anti-tumor immunity. GCs profoundly reshape the tumor immune microenvironment (TIME) by suppressing cytotoxic T-cell activity, enhancing regulatory T cells, polarizing macrophages toward tumor-promoting states, inhibiting NK and dendritic cell function, and expanding myeloid-derived suppressor cells. Together, these alterations weaken immune surveillance and may promote tumor progression, metastasis, and therapeutic resistance. Both systemic and tumor-derived GC signaling further interact with niches that sustain cancer stemness. Clinical data indicate that the timing, dose, and duration of steroid exposure are decisive, with early or high-dose administration frequently associated with poorer immunotherapy outcomes. Therefore, clarifying GC-driven immune modulation is critical to balance toxicity control while preserving anti-tumor efficacy in precision immunotherapy.
    Keywords:  Cancer progression; Glucocorticoids; Immunosuppression; Immunotherapy; Steroid signaling; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.106978
  14. Hepatol Int. 2026 Mar 04.
    ZG16 represses tumor progression and M2 polarization of tumor-associated macrophages in hepatocellular carcinoma by promoting ubiquitination and degradation of SNX9 via binding to ITCH.
    Hui Meng, Zeyuan Wang, Liye Wang, Xiaokun Fang, Haonan Li, Weiqian Ma, Yi Ding, Manman Nan, Yu Meng, Ling Li, Yizhen Li, Kuisheng Chen, Mingzhi Zhang.
       BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive primary liver malignancy characterized by limited therapeutic options and poor prognosis. Within the tumor microenvironment (TME), tumor-associated macrophages (TAMs) predominantly exhibit an M2-like phenotype, contributing to immune escape and tumor progression. Zymogen granule protein 16 (ZG16) has been reported to be downregulated in HCC, but its precise biological function and molecular mechanisms remain poorly understood. Therefore, we aimed to investigate the impact of ZG16 on HCC cell metastasis and TAM infiltration, as well as to elucidate its molecular mechanism.
    METHODS: Gain- and loss-of-function assays were used to verify the effect of ZG16 on HCC cell metastasis, as well as the recruitment and M2 polarization of TAMs. The underlying mechanism of ZG16 was explored by immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC/MS) analysis, co-immunoprecipitation (co-IP) assay, and GST pull-down assay.
    RESULTS: Our results demonstrated that ZG16 overexpression significantly inhibited metastasis of HCC cells while also suppressing the recruitment and M2 polarization of TAMs, suggesting its dual role in both tumor cell-intrinsic and microenvironmental regulation. Notably, sorting nexin 9 (SNX9), a facilitator of HCC, was identified as a downstream target of ZG16. Mechanistically, we uncovered that ZG16 physically interacted with SNX9 and promoted its protein degradation through the ubiquitin-proteasome pathway. Functional rescue experiments provided compelling evidence that SNX9 overexpression effectively counteracted ZG16-mediated suppression of both HCC progression and TAM M2 polarization. Further mechanism exploration confirmed that ZG16 promoted the ubiquitination and degradation of SNX9 by recruiting itchy E3 ubiquitin protein ligase (ITCH).
    CONCLUSIONS: Our findings certify that ZG16 suppresses tumor progression and M2 polarization of TAMs in HCC through ITCH-mediated ubiquitination and subsequent degradation of SNX9. The ZG16/ITCH/SNX9 axis may represent an important regulatory pathway and potential therapeutic target for HCC.
    Keywords:  Hepatocellular carcinoma; ITCH; SNX9; Tumor-associated macrophages; ZG16
    DOI:  https://doi.org/10.1007/s12072-026-11067-7
  15. Zhongguo Fei Ai Za Zhi. 2025 Dec 20. 28(12): 948-955
    [Research Advances on the Immune Evasion Mechanisms of Disseminated Tumor Cells and Their Roles in Cancer Metastasis].
    Zujun Que, Bin Luo, Jianhui Tian.
      Tumor metastasis is the leading cause of cancer-related mortality. Disseminated tumor cells (DTCs), serving as the critical 'seeds' in the metastatic cascade, hold the key to determining the success or failure of metastasis. Following dissemination from the primary tumor and colonization of distant organs, DTCs often enter a prolonged state of dormancy. Their subsequent escape from immune surveillance through sophisticated mechanisms enables them to transition from this dormant state to a proliferative one, ultimately culminating in clinically detectable metastatic lesions. A profound understanding of DTCs immune evasion is therefore essential for unraveling the fundamental biology of metastasis and developing effective anti-metastatic strategies. This article systematically reviewed the latest advances in the mechanisms underlying DTCs immune evasion, focusing on three core aspects: defects in antigen presentation, formation of an immunosuppressive microenvironment, and metabolism reprogramming-mediated immunosuppression. Specifically, DTCs achieve 'immune invisibility' by downregulating major histocompatibility complex class-I (MHC-I) molecule expression; they actively construct a local 'protective shield' by recruiting immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs); and they impair effector immune cell function at the energetic and metabolic levels by remodeling glucose, amino acid, and lipid metabolism. Building upon this, we innovatively integrate the traditional Chinese medicine (TCM) theories of 'hidden toxicity due to vital qi deficiency' and the 'metastatic state' to elucidate the dynamic pathogenic relationship between the body's systemic 'Zhengqi' (vital energy) status and the dormancy-awakening switch of DTCs, offering a novel holistic perspective for comprehending the metastatic process. Finally, we discussed the prospects of multi-target combination therapeutic strategies against DTCs immune evasion and highlight the potential of emerging technologies, such as single-cell sequencing and spatial transcriptomics, aiming to provide valuable insights for future in-depth research and clinical translation in the field of anti-metastasis therapy.
.
    Keywords:  Disseminated tumor cells; Hidden toxicity due to vital qi deficiency; Immune evasion; Metastatic state; Tumor metastasis
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2025.101.23
  16. Front Immunol. 2026 ;17 1768606
    Targeting cellular source-specific CXCL9 signaling for immunotherapy in oral squamous cell carcinoma.
    Miao Qiu, Ling Wang, Honglin Tang, Shan Jiang.
      Oral squamous cell carcinoma (OSCC) remains a clinical challenge due to its high recurrence, metastatic potential, and limited responsiveness to current immunotherapies. Within the tumor microenvironment (TME), the C-X-C motif chemokine ligand 9 (CXCL9) plays a pivotal yet paradoxical role, functioning as both an anti-tumor effector and a tumor-promoting factor depending on its cellular origin. This review proposes that the function of CXCL9 is not intrinsic but dictated by the interplay among its cellular source, microenvironmental context, and receptor-expressing cells. We delineate how this tripartite crosstalk influences immune checkpoint blockade (ICB) outcomes through mechanisms such as T-cell suppression, regulatory T cells recruitment, and PD-L1 upregulation. Myeloid cell-derived CXCL9 generally mediates anti-tumor immunity by recruiting cytotoxic lymphocytes, whereas CXCL9 produced by stromal cells like cancer-associated fibroblasts often contributes to metastasis and immune evasion. Given this complexity and unique immunosuppressive and fibrotic properties of OSCC, we argue that simply augmenting or blocking CXCL9 is insufficient. Instead, overcoming ICB resistance in OSCC requires a precision strategy focused on targeting cell-specific CXCL9 signaling. Ultimately, dissecting and therapeutically navigating the source-specific CXCL9 network is essential to transform the OSCC TME and improve clinical outcomes.
    Keywords:  CXCL9; fibroblast; immune checkpoint blockade; oral squamous cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1768606
  17. Cancer Control. 2026 Jan-Dec;33:33 10732748261430581
    Research Progress on Tumor-Associated Macrophages and PD-1/PD-L1 Inhibitors in Advanced Colorectal Cancer.
    Shihao Ning, Huiming Wu, Renkai Guo, Min Deng, Yipeng Cui, Dingwen Xue, Chunchen Li, Chenfei Jin, Huiyu Li.
      Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related mortality worldwide. Currently, surgical resection remains the cornerstone of curative treatment for CRC; however, patients with advanced disease continue to face significant risks of postoperative recurrence and metastasis. Although immune checkpoint inhibitors (ICIs), represented by PD-1/PD-L1 monoclonal antibodies, have reshaped the therapeutic landscape of various solid tumors, their clinical benefit in CRC is strictly limited by mismatch repair (MMR) status, leaving the vast majority of proficient mismatch repair/microsatellite stable (pMMR/MSS) patients with minimal therapeutic gain. Importantly, tumor-associated macrophages (TAMs)-a key regulatory component of the tumor immune microenvironment-not only exert immunosuppressive functions through PD-1 and multiple other pathways, but also promote PD-1 expression on tumor cells via distinct mechanisms. Consequently, accumulating evidence suggests that TAMs play a critical role in mediating resistance to PD-1/PD-L1 inhibitors in CRC. Nevertheless, research on the underlying mechanisms remains at an early stage. This narrative review aims to summarize the latest advances regarding the involvement of TAMs in resistance to PD-1/PD-L1 blockade, with a particular focus on strategies to enhance immunotherapy responsiveness through TAM modulation. We further discuss limitations in current clinical studies and propose potential directions for future research. By juxtaposing successful mechanistic studies with underwhelming clinical trial data, we aim to redefine the therapeutic rationale for combining TAM-targeted agents with immune checkpoint blockade.
    Keywords:  colorectal neoplasms; immune checkpoint inhibitors; immune checkpoint proteins; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748261430581
  18. Oncoimmunology. 2026 Dec 31. 15(1): 2640261
    Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models.
    Nuri Sung, Eunsu Kim, Yosef Gilad, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han.
      Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8+, CD4+, and natural killer (NK) immune cells into the tumor microenvironment (TME). Given the anti-tumor effects of SRC-3KO Tregs in two different solid cancers, we sought to extend our studies to additional cancer types. Here, we showed that SRC-3KO Tregs exerted a potent antitumor immunity-like effect, capable of eradicating glioblastoma, melanoma, and lung cancer in their respective syngeneic mouse models by generating an anti-tumor immune environment. These results support the translational development of SRC-3-targeted Treg modulation as a safe and effective immunotherapy platform for treatment-refractory cancers.
    Keywords:  Regulatory T cells; glioblastoma; lung cancer; melanoma; steroid receptor coactivator 3; syngeneic murine cancer models
    DOI:  https://doi.org/10.1080/2162402X.2026.2640261
  19. Cancer Metastasis Rev. 2026 Mar 02. pii: 10. [Epub ahead of print]45(1):
    CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond.
    Jeremy Wells, Ajay Gupta.
      CAR-T cell therapy, which uses endogenous T cells engineered to target specific cancer antigens, is one of the most promising recent developments in the treatment of hematologic malignancies in both children and adults. CAR-T cells have shown tremendous success in treating B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma, and they are currently FDA-approved for the treatment of six hematologic malignancies. Its success in solid tumors has been more modest, which has been attributed to several factors including the hostile tumor microenvironment (TME), poor persistence of CAR-T cells, and difficulty directing CAR-T cells towards solid tumors. Armored CAR-T cells, which modify the TME via secreted cytokines, have shown early success in the treatment of solid pediatric malignancies. We review recent trials of CAR-T cells to treat common pediatric solid malignancies, including Ewing sarcoma, osteosarcoma, neuroblastoma, diffuse intrinsic pontine glioma, rhabdomyosarcoma, Wilms tumor, and retinoblastoma. We focused particularly on armored CAR-T cells where applicable. Armored CAR-T cells have been utilized to target a variety of tumor-associated antigens on pediatric solid tumors with early successes both in vivo and in vitro, and innovative approaches for addressing their limitations are rapidly being developed.
    Keywords:  CAR-T; Immunotherapy; Pediatric; Solid; Tumor
    DOI:  https://doi.org/10.1007/s10555-026-10317-2
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