bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–04–19
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Tumor microenvironment-induced epigenetic reprogramming of Tregs and its impact on immunotherapy.
  2. Myeloid derived suppressor cells in neuroblastoma: mechanisms of immune evasion and therapeutic opportunities.
  3. Hypoxic microenvironment in cancer: role in metabolic reprogramming.
  4. Nanodelivery of Traditional Chinese Medicine Monomers: An Emerging Strategy to Reprogram the Immunosuppressive Tumor Microenvironment.
  5. VPS34 in Autophagy, Cancer, and Cancer Therapy.
  6. Acupuncture in remodeling the tumor microenvironment: current status and challenges.
  7. Metabolic regulation of tumor-associated macrophage function and immunotherapy in cancer.
  8. Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.
  9. Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.
  10. Targeting PSMD14 enhances immunotherapy efficacy by promoting PD-L1 degradation and reshaping the tumor microenvironment in breast cancer.
  11. Neutrophil extracellular traps in the tumor microenvironment, metastasis, therapy, and beyond: advances, challenges, and perspectives.
  12. Pan-cancer macrophage atlas uncovers that MHC-IIhigh TAMs induce Treg activation through physical interactions.
  13. Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.
  14. AllergoOncology: Emerging Translational and Clinical Significance of Basophils and Mast Cells in Cancer.
  15. [Advances in Lactate Metabolic Reprogramming in Non-small Cell Lung Cancer].
  16. Macrophage plasticity in the osteosarcoma tumor microenvironment: opportunities and challenges for immunotherapy.
  17. Mucosal immunity in cancer metastasis: roles, mechanisms, and therapeutic implications.
  18. On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.
  19. Solute Carrier Transporters in Tumor Metabolism and Tumor Immunity.
  20. Complex Features of Tumor-Infiltrating Lymphocytes (TILs) and Stromal Response After Neoadjuvant Breast Chemotherapy.
  21. Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.
  1. Front Genet. 2026 ;17 1787421
    Tumor microenvironment-induced epigenetic reprogramming of Tregs and its impact on immunotherapy.
    Wenhao Li, Jiyu Tong.
      The tumor microenvironment (TME) represents a complex system comprising various cells and extracellular matrix components that play a crucial role in tumor initiation and progression. While recent therapeutic strategies for predominantly focus on targeting tumor cells, their impact on other cellular components in the TME, such as regulatory T (Treg) cells, remains insufficiently understood. The cellular components of the TME include tumor cells, immune cells, tumor-associated stromal cells, and myeloid-derived suppressor cells. Notably, the role of Treg cells in tumor therapy has emerged as a significant research area of focus in recent years. Regulatory CD4+ T cells, characterized by the expression of the transcription factor Forkhead Box P3 (FOXP3) and the surface marker CD25, are pivotal in mediating immune suppression and maintaining immune tolerance and homeostasis. Current tumor treatments mainly rely on radiation and chemotherapy. Although innovative therapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated promising outcomes, their efficacy is limited, benefiting only a small subset of patients. Epigenetic inhibitors are increasingly recognized as pivotal in cancer treatment; however, prior research has predominantly concentrated on their effects on the tumor itself, while overlooking the potential influence of these compounds on regulatory T cells (Tregs) within the tumor microenvironment (TME). The therapeutic viability of modulating Tregs within the TME remains uncertain. The intricate microenvironment of the TME significantly influences the distinct epigenetic landscape of tumor-infiltrating Treg cells, including modifications in DNA methylation, histone modifications, and chromatin remodeling. A comprehensive understanding of these epigenetic modifications and the underlying factors driving them could unveil novel strategies for cancer therapy. This approach would enhance the understanding of the critical role of Tregs in tumor therapy and facilitate the development of more effective targeted therapies by addressing the unique epigenetic characteristics of tumor-infiltrating Tregs.
    Keywords:  Tregs; epigenetic; epigenetic regulation; tumor macroenvironment; tumor therapy
    DOI:  https://doi.org/10.3389/fgene.2026.1787421
  2. Front Immunol. 2026 ;17 1773622
    Myeloid derived suppressor cells in neuroblastoma: mechanisms of immune evasion and therapeutic opportunities.
    Hae Soo Choo, Tina Yu, Timothy Pham, Neharika Singh, Shweta Joshi.
      Neuroblastoma is the most common extracranial pediatric solid tumor. Although the incorporation of anti-GD2 immunotherapy into standard care has improved outcomes, five-year survival for high-risk patients remains below 50%. This highlights that, while immunotherapy holds promise in this pediatric cancer, neuroblastoma has developed multiple immunosuppressive mechanisms that limit anti-tumor immune responses. Among these, myeloid cells, including tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a central role in promoting tumor progression and suppressing immune activity. MDSCs, which are primarily classified into monocytic (M-MDSC) and granulocytic (PMN-MDSC) subsets, are markedly increased in both murine neuroblastoma models and human patients, where they promote immunosuppression and impair T cell and NK cell functions. This review summarizes the myeloid landscape in neuroblastoma, covering the origin and development of MDSCs, the phenotypic and functional diversity of MDSC subsets, the mechanisms driving MDSC recruitment and immunosuppressive activity, and emerging therapeutic strategies to enhance immunotherapy efficacy, including approaches to target MDSCs and modulate ferroptosis to reprogram their function.
    Keywords:  Immunosuppression; myeloid cells; myeloid derived suppressor cells; neuroblastoma; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1773622
  3. Front Oncol. 2026 ;16 1771365
    Hypoxic microenvironment in cancer: role in metabolic reprogramming.
    Niti Sureka, Rashi Maheshwari, Amit Agravat, Shweta Singhal, Shamsuz Zaman, Bhavika Rishi, Fouzia Siraj, Sufian Zaheer, Aroonima Misra.
      Hypoxia, a defining hallmark of solid tumors, arises from structurally and functionally abnormal vasculature, rapid cellular proliferation, and impaired perfusion, resulting in chronic and cycling oxygen deprivation within the tumor massThe hypoxic tumor microenvironment orchestrates extensive molecular reprogramming primarily through stabilization and activation of hypoxia-inducible factors (HIF-1α and HIF-2α), which regulate broad transcriptional networks governing metabolism, angiogenesis, stemness, invasion, and immune modulation. Under low oxygen tension, tumor cells shift toward aerobic glycolysis, enhance glutamine utilization, promote lipid synthesis and storage, suppress mitochondrial oxidative phosphorylation, and fine-tune redox balance through coordinated regulation of ROS-generating and antioxidant systems. These adaptations not only sustain proliferation and survival under metabolic stress but also facilitate epithelial-mesenchymal transition, extracellular matrix remodeling, and metastatic dissemination. Beyond malignant cells, hypoxia reprograms stromal compartments-including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages, and myeloid-derived suppressor cells-thereby establishing a metabolically cooperative, angiogenic, and profoundly immunosuppressive microenvironment. Hypoxia-induced acidosis, lactate accumulation, and HIF-driven cytokine signaling further impair cytotoxic T-cell and NK-cell activity, contributing to immune escape and resistance to radiotherapy, chemotherapy, and immunotherapy. Emerging evidence from single-cell multi-omics, spatial transcriptomics, metabolic imaging, and early-phase clinical trials targeting HIF signaling, angiogenic pathways, and metabolic enzymes has uncovered actionable vulnerabilities in hypoxia-driven malignancies. This review synthesizes the mechanistic foundations of hypoxia-induced metabolic reprogramming, its role in tumor progression and therapeutic resistance, and discusses innovative strategies aimed at exploiting hypoxia-associated metabolic dependencies to advance precision oncology.
    Keywords:  Warburg effect; hypoxia; hypoxia-inducible factors (HIFs); immune evasion; metabolic reprogramming; mitochondrial metabolism; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2026.1771365
  4. Int J Nanomedicine. 2026 ;21 576928
    Nanodelivery of Traditional Chinese Medicine Monomers: An Emerging Strategy to Reprogram the Immunosuppressive Tumor Microenvironment.
    Lin Zhong, Minyan Xing, Jiaze Yu, Xuqi Sun, Xiaomeng Dai, Xuanwen Bao, Chenping Huang, Jing Han, Jianping Li, Peng Zhao.
      The tumor microenvironment (TME), a highly complex and dynamic system, plays a central role in tumor progression and resistance to immunotherapy. Key immunosuppressive cell populations within the TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), contribute to immune evasion through complex cytokine signaling and cellular crosstalk. These factors significantly limit the therapeutic efficacy of immune checkpoint inhibitors and other immunotherapies, particularly in "cold" tumors with poor immune infiltration. Traditional Chinese medicine (TCM) monomers have emerged as promising immunomodulatory agents due to their multi-target capability, favorable safety profiles, and ability to remodel the immune landscape. TCM compounds such as curcumin, berberine, resveratrol, and ginsenosides can modulate the recruitment, polarization, or function of TAMs, MDSCs, and Tregs. However, their clinical translation is hindered by the central challenge of poor solubility, low bioavailability, and limited tumor targeting capability. Nanotechnology provides a breakthrough strategy to address this core issue. Recent advances in nanotechnology offer effective solutions by enabling the encapsulation of TCM monomers into nano-delivery systems such as liposomes, polymeric nanoparticles, inorganic carriers, and biomimetic vesicles which enhance drug stability, promote tumor-specific accumulation, and allow controlled release. These integrated systems potentiate the pharmacological effects of TCM agents. Moreover, they help overcome immune resistance mechanisms within the TME. This review systematically examines the immunosuppressive roles of TAMs, MDSCs, and Tregs, summarizes the immunoregulatory actions of TCM monomers, and highlights cutting-edge nano-formulations developed to optimize their delivery. Together, these insights offer a novel framework for developing TCM-based nanomedicine strategies aimed at reprogramming the immunosuppressive TME and enhancing cancer immunotherapy.
    Keywords:  nano-delivery systems; traditional Chinese medicine monomer; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S576928
  5. Cells. 2026 Apr 01. pii: 636. [Epub ahead of print]15(7):
    VPS34 in Autophagy, Cancer, and Cancer Therapy.
    Elisabetta Bartolini, Bassam Janji, Ruize Gao.
      Autophagy is a fundamental lysosome-dependent degradation process that maintains cellular homeostasis in response to stress. VSP34 (Vacuolar Protein Sorting 34, PIK3C3) is the only class-III phosphatidylinositol 3-kinase and generates phosphatidylinositol 3-phosphate (PI3P) for auto-phagosome nucleation and maturation. Thus, it provides a critical adaptive survival pathway for cells that are experiencing metabolic stress. The VPS34-autophagy axis plays dual roles in cancer, which depend on the context: it can restrain early tumorigenesis, but in established tumors, it can promote survival in conditions of hypoxia, nutrient deprivation, and therapeutic pressure. Moreover, VPS34 shapes the tumor microenvironment (TME) through its influence on both immune and cancer cells by modulating autophagy, cGAS-STING (cyclic GMP-AMP synthase Stimulator of Interferon Genes), and STAT1 pathways. VPS34 inhibition has been reported to induce an interferon response that increases CD8+ T and natural killer (NK) cell infiltration and converts cold tumors into hot ones. This behavior suggests that combining VPS34 inhibitors with cancer immunotherapies could be beneficial. In this review, we summarize the molecular functions and regulations of VPS34 in autophagy and discuss recent advances linking VPS34 to tumor and cancer immunotherapy.
    Keywords:  VPS34; autophagy; cancer immunity; cancer immunotherapy; cancer therapy; immunity
    DOI:  https://doi.org/10.3390/cells15070636
  6. Front Immunol. 2026 ;17 1737746
    Acupuncture in remodeling the tumor microenvironment: current status and challenges.
    Jinming Liu, Yanjun Jin, Yan Ou, Linbo Liu, Shanqi Guo, Binxu Sun.
      The tumor microenvironment (TME) is a dynamic ecosystem in which malignant, immune, stromal, and vascular compartments continuously interact, and plays a key role in tumor initiation, development and treatment resistance. In recent years, acupuncture, as an ancient neuromodulatory intervention means of traditional medicine, has shown promise in supportive oncology by attenuating chemotherapy- and radiotherapy-induced toxicities, modulating immunity, and improving quality-of-life metrics. Yet, a mechanistic framework that links acupuncture to TME reprogramming remains to be established. From the perspective of TME, we reviews the latest research status of acupuncture anti-tumor mechanism. Evidence synthesized indicates that acupuncture (i) triggers apoptosis of malignant cells, (ii) re-educates innate (NK, macrophage, dendritic, and mast) and adaptive (T and B lymphocyte) immune subsets, and (iii) normalizes tumor vasculature, so as to inhibit tumor growth and metastasis, synergize chemotherapy and immunotherapy, and promote physical rehabilitation. We further outline opportunities and challenges for translating acupuncture into evidence-based oncology. Using breast cancer as a paradigm, we emphasize the need to evaluate the role of acupuncture in different molecular subtypes and within integrative survivorship care. Furthermore, we aim to link its benefit of relieving symptoms with TME modulation mechanisms, thereby constructing an integrated evidence chain connecting "clinical symptoms-acupuncture intervention-TME modulation-long-term prognosis.". Interdisciplinary trials that couple mechanistic TME readouts with robust clinical endpoints are now warranted to definitively establish the efficacy and safety of acupuncture in cancer care.
    Keywords:  acupuncture; breast cancer; clinical symptoms; mechanism; review; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1737746
  7. Cancer Biol Med. 2026 Apr 13. pii: j.issn.2095-3941.2025.0626. [Epub ahead of print]
    Metabolic regulation of tumor-associated macrophage function and immunotherapy in cancer.
    Mingyue Zhao, Rui Chen, Ping Gao.
      Tumor-associated macrophages (TAMs), essential components of the tumor immune microenvironment (TIME), undergo metabolic reprogramming as part of functional adaptation. Tumor cells modulate TAMs through multiple mechanisms, including metabolic cross-feeding, cytokine production, extracellular vesicles, tumor-derived proteins (such as GRP78) and pathogen-associated patterns (such as Lipopolysaccharide) signaling mediators. In turn, metabolic alterations in TAMs fine-tune TAM function via intricate signaling networks with outcomes that vary across cancer types. These functional and phenotypic shifts enable TAMs to influence malignant cells and other TIME components, such as T cells, NK cells, and fibroblasts, through the secretion of inflammatory factors and changes in surface marker expression. This process establishes an extensive network of interconnected cellular crosstalk. In this review the metabolic alterations-intracellular signaling-TAM biology axis is linked to cancer progression contributions and the implications for immunotherapy across diverse malignancies. Building on these insights, current preclinical and clinical studies with a focus on TAMs were surveyed and the advantages and challenges of TAM-targeted therapeutic strategies were systematically evaluated. We anticipate that these perspectives will spur further investigation into TAM-specific immune targets and accelerate the development of next-generation cancer immunotherapies.
    Keywords:  Tumor-associated macrophage; immunotherapy; metabolic rewiring; tumor microenvironment
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0626
  8. bioRxiv. 2026 Apr 06. pii: 2026.04.02.716169. [Epub ahead of print]
    Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.
    Rashi Singhal, Nina W Zhang, Zheng Hong Lee, Hannah N Bell, Prarthana J Dalal, Sumeet Solanki, Wesley Huang, Ryan Rebernick, Peter Sajjakulnukit, Himani Jasewicz, Roshan Kumar, Nikhil K Kotla, Amanda Huber, Anitha Vijay Mallappa, Subhash B Arya, Shogo Takahashi, Carlos Ichiro Kasano-Camones, Eileen Carpenter, Marina Pasca di Magliano, James J Moon, Carole A Parent, Frank J Gonzalez, Andrew D Patterson, Michael D Green, Weiping Zou, Elena M Stoffel, Costas A Lyssiotis, Yatrik M Shah.
      As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPARα activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.
    DOI:  https://doi.org/10.64898/2026.04.02.716169
  9. Mol Oncol. 2026 Apr 17.
    Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.
    Kanishka Tiwary, Jose Javier Bravo-Cordero.
      Metastasis remains the leading cause of cancer-related mortality. Even after major advances in early detection and systemic therapies, long-term disease recurrence frequently arises from the presence of dormant disseminated tumor cells (DTCs) at distant sites. Dormant DTCs disseminate from the primary tumor and reside in secondary organs in a reversible quiescent state characterized by minimal proliferation, enabling resistance to therapies that target actively dividing cells. Despite their inactivity, dormant DTCs are far from inert. Dormant DTCs dynamically interact with the surrounding tumor microenvironment (TME), including stromal, vascular, and immune components, to establish niches that maintain quiescence while limiting immune detection. While the mechanisms by which proliferating cancer cells evade immune surveillance have been extensively studied, the processes governing immune regulation, immune-mediated dormancy, and immune evasion of dormant DTCs remain incompletely integrated across literature. In this review, we explore recent advances describing how microenvironmental cues and immune pressures converge on tumor cell-intrinsic programs to sustain dormancy, promote immune tolerance, and enable long-term survival of DTCs across different organs and cancer types. We further discuss conditions that disrupt this equilibrium and drive escape from dormancy, as well as emerging therapeutic strategies aimed at eliminating or controlling dormant DTCs by targeting dormancy-specific immune and microenvironmental interactions.
    Keywords:  disseminated tumor cells; immune evasion; metastatic niche; quiescence; tumor dormancy; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70259
  10. J Exp Clin Cancer Res. 2026 Apr 14.
    Targeting PSMD14 enhances immunotherapy efficacy by promoting PD-L1 degradation and reshaping the tumor microenvironment in breast cancer.
    Shichao Wen, Yuhan Liu, Qi Liu, Liqian Su, Yuhua Wang, Yiqiu Ma, Jingxuan Wang.
      
    Keywords:  Breast cancer; Deubiquitination; Immunotherapy; PD-L1; PSMD14; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-026-03710-w
  11. J Hematol Oncol. 2026 Apr 15.
    Neutrophil extracellular traps in the tumor microenvironment, metastasis, therapy, and beyond: advances, challenges, and perspectives.
    Jingwen He, Zhaokai Zhou, Guangyang Cheng, Huabing Li, Jiaqi Tu, Zixuan Fan, Xiuting Qiu, Wenjie Chen, Yajun Chen, Ling Li, Chen Li, Zhengrui Li, Lina Chen, Qiong Lu.
      Neutrophil extracellular traps (NETs), the DNA-protein structures released by neutrophils within the tumor microenvironment (TME), play a role in cancer that extends far beyond their traditional antimicrobial function. Specifically, NETs exert multifaceted and context-dependent effects on tumor progression, metastasis, immune regulation, and therapeutic response, showing their robust activity in shaping the complex landscape of tumor biology. This review systematically elucidates how NETs promote tumorigenesis by inducing DNA damage and epithelial-mesenchymal transition (EMT), and drive metastatic spread through mechanisms such as trapping circulating tumor cells, remodeling the pre-metastatic microenvironment, and reactivating dormant cells. Concurrently, NETs shape an immunosuppressive TME by modulating T cells, NK cells, and macrophages, while mediating resistance to chemotherapy, radiotherapy, and immunotherapy. Based on these mechanisms, targeting NET formation (such as inhibiting PAD4 or NE) or degrading their structures (such as using DNase I) has emerged as a potential strategy to enhance the efficacy of existing therapies. Therefore, deepening the understanding of the multifunctional regulatory networks underlying NETs within the TME holds significant implications for developing novel precision cancer therapies.
    Keywords:  Cancer; Metastasis; Neutrophil extracellular traps; Neutrophils; Treatment resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-026-01789-4
  12. Cell Rep. 2026 Apr 10. pii: S2211-1247(26)00308-6. [Epub ahead of print]45(4): 117230
    Pan-cancer macrophage atlas uncovers that MHC-IIhigh TAMs induce Treg activation through physical interactions.
    Naixue Yang, Hao Yuan, Wei Wang, Xinquan Liu, Chang Liu, Yi Yao, Yue Li, Yibo Gao, Xin Lin, Mingchao Wang, Xun Lan.
      Dendritic cells (DCs) are recognized as the primary antigen-presenting cells (APCs) within the tumor microenvironment (TME), orchestrating T cell responses via the major histocompatibility complex class II (MHC-II). However, the contribution of tumor-associated macrophages (TAMs) to antigen presentation within the TME remains largely unexplored. By integrating single-cell RNA-seq data from 10 cancer types, we discover that tumor-enriched TAMs universally exhibit elevated phagocytosis and MHC-II-mediated antigen presentation, distinct from canonical tumor-promoting M2 macrophages. Notably, MHC-IIhigh TAMs preferentially interact with regulatory T cells (Tregs) across cancers. Using a mouse model of lung adenocarcinoma, we demonstrate that MHC-IIhigh TAMs promote Treg activation and expansion through antigen presentation and direct contact, while their depletion restrains Treg activation and suppresses tumor growth. Moreover, clinical datasets from patients receiving immunotherapy reveal that the presence of MHC-IIhigh TAMs correlates with immunotherapy resistance. Together, these findings redefine macrophage antigen presentation in the TME and reveal new therapeutic opportunities.
    Keywords:  CP: cancer; CP: immunology; MHC-II; Tregs; single-cell RNA-seq; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.celrep.2026.117230
  13. Front Immunol. 2026 ;17 1760809
    Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.
    Hannah Elaine Smid, Jana Colotti, Sophia Nölp, Nike Sophia Arlt, Sophie Weber, Amelie Gumann, Stephan von Hörsten, Axel Karow, Wolfgang Schuh.
      Glutaminyl-peptide cyclotransferase (QPCT, QC) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL, isoQC) are zinc-dependent enzymes that post-translationally catalyze the conversion of N-terminal glutamine or glutamate residues into pyroglutamate (pGlu). The pGlu modification impacts protein-protein interactions, enhances protein stability, and protects proteins from proteolytic degradation. QPCTL and QPCT differ in their subcellular localization, with QPCTL being retained in the Golgi apparatus and QPCT being active in secretory vesicles. Current research focuses on the impact of QPCTL-mediated pGlu formation in cancer and neurodegenerative disorders such as Alzheimer's disease. In cancer, QPCTL is a promising immunotherapy target since QPCTL-mediated CD47 pyroglutamylation prevents macrophages from phagocytosing tumor cells. Moreover, QPCTL shapes the tumor microenvironment by modulating macrophage recruitment and polarization through modification of CCL2. However, QPCTL modulates Butyrophilins on tumor cells and thereby promote their detection and killing by γδ T cells. Hence, QPCTL significantly affects cancer progression, inflammatory processes, and immune regulation. These insights highlight QPCTL's potential as a therapeutic target in oncology, metabolic diseases, and immune-mediated disorders. In this review, we highlight the role of QPCTL in tumor evasion and immune modulation. Moreover, we provide a comprehensive overview about predicted and validated substrates of QPCT/L and about the relevance of QPCT/L in various diseases.
    Keywords:  IsoQC; QC; QPCT; QPCTL; glutaminyl cyclases; immune cells; pyroglutamate
    DOI:  https://doi.org/10.3389/fimmu.2026.1760809
  14. Clin Transl Allergy. 2026 Apr;16(4): e70170
    AllergoOncology: Emerging Translational and Clinical Significance of Basophils and Mast Cells in Cancer.
    Jack Alder, Katie E Lacy, Debra H Josephs, James Spicer, Heather J Bax, Sophia N Karagiannis, Jitesh Chauhan.
      Mast cells and basophils, historically defined by their pathogenic roles in allergic diseases and type I hypersensitivity, are increasingly recognized as influential participants in cancer biology. Emerging research in AllergoOncology highlights their plasticity, diverse functions, and significance beyond classical contributions to allergy. This review summarizes current evidence on their presence, activation states, and roles across multiple cancer types. We examine their interactions with other immune populations, their context-dependent pro- and anti-tumor functions, and their potential utility as biomarkers. Their pro-tumor activities include secretion of Th2 cytokines, release of angiogenic mediators, and facilitation of extracellular matrix remodeling, all of which can support tumor progression. Conversely, these cells may also promote anti-tumor immunity through effector mechanisms and recruitment of cytotoxic CD8+ T cells. Translational tools such as the basophil activation test (BAT) and the mast cell activation test (MAT) are emerging to help predict hypersensitivities to cancer treatments including immunotherapies. A deeper understanding of their dynamic roles within the tumor microenvironment (TME) and across anatomical locations may reveal previously underappreciated functions, prognostic value, and therapeutic opportunities.
    Keywords:  AllergoOncology; basophils; cancer immunotherapy; mast cells; tumor immunology
    DOI:  https://doi.org/10.1002/clt2.70170
  15. Zhongguo Fei Ai Za Zhi. 2026 Feb 20. 29(2): 141-149
    [Advances in Lactate Metabolic Reprogramming in Non-small Cell Lung Cancer].
    Jun Zhou, Liuling Ge, Jingting Jiang.
      Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality, with a low five-year survival rate. Lactate metabolism plays a central role in the metabolic reprogramming of NSCLC. Beyond serving as the end-product of glycolysis, lactate accumulates in the tumor microenvironment (TME), contributing to acidification, and can also enter the tricarboxylic acid cycle to participate in energy metabolism. Moreover, the G protein-coupled receptor 81 (GPR81)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling axis induces the expression of immune checkpoint molecules, such as programmed death-ligand 1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), thereby suppressing the functions of T lymphocytes and natural killer cells and establishing an immunosuppressive microenvironment. Lactate further promotes epithelial-mesenchymal transition and tumor metastasis, and drives NSCLC chemoresistance and relapse via histone lactylation. Clinical studies indicate that enhanced lactate metabolism is associated with NSCLC progression and chemotherapy resistance, while targeting lactate metabolism in combination with immunotherapy exerts synergistic antitumor effects. Therefore, comprehensive inhibition of lactate metabolism together with enhancement of antitumor immunity may improve the efficacy of precision therapy in NSCLC.
.
    Keywords:  Epigenetics; Lactate metabolism; Lung neoplasms; Tumor microenvironment
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2026.106.03
  16. J Cancer Res Clin Oncol. 2026 Apr 13. pii: 88. [Epub ahead of print]152(4):
    Macrophage plasticity in the osteosarcoma tumor microenvironment: opportunities and challenges for immunotherapy.
    Haifeng Li, Chengri Liu, Baojian Zhang, Yanhu Zhang, Yanqun Liu.
      
    Keywords:  Immunotherapy; Macrophage plasticity; Osteosarcoma; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00432-026-06471-3
  17. Front Immunol. 2026 ;17 1809558
    Mucosal immunity in cancer metastasis: roles, mechanisms, and therapeutic implications.
    Yaru Miao, Dongdong Cui, Yanghui Bi, Ruiping Zhang.
      Previous studies have shown that the mucosal immune system plays a crucial role in regulating immune tolerance, maintaining the integrity of the mucosal barrier, and facilitating immune communication between organs. However, its role in tumor metastasis has not been fully investigated. This review integrates recent studies on mucosal immunity and tumor metastasis, systematically discussing the process by which mucosal immune dysregulation promotes tumor metastasis. We elucidate how the mucosal imprinting program formed within the common mucosal immune system affects metastasis through regulating immune tolerance, tissue-specific homing, and the circulating adaptability of metastatic tumor cells. During this process, the microbiota within the tumor also plays an important synergistic role. Through major mucosal axes such as the gut-lung axis and the gut-liver axis, damaged mucosal immunity remodels the composition and metabolic state of tissue-resident immune cells and remotely regulates the pre-metastatic microenvironment. At the distal mucosal sites, immune populations such as alveolar macrophages and tissue-resident memory T cells inhibit tumor metastasis growth by forcing tumor dormancy, maintaining mucosal immune balance. However, when the body experiences a chronic infection and the mucosal immune system is disrupted, dormant tumor cells can be reactivated for metastasis. This review describes the roles of mucosal immunity at different stages of tumor metastasis, providing a reference for understanding the role of mucosal immunity in tumor metastasis and revealing the key mechanism pathways and therapeutic strategies for preventing metastasis recurrence.
    Keywords:  immune tolerance; microbiota; mucosal immunity; pre-metastatic niche; tissue-resident immunity; tumor metastasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1809558
  18. Sci Transl Med. 2026 Apr 15. 18(845): eadu3532
    On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.
    Junya Yamaguchi, Keisuke Watanabe, Akihiro Nakamura, Nina Yi-Tzu Lin, Sachi Maeda, Daisuke Sugiyama, Shinichiro Kato, Akihito Nagata, Hitomi Nishinakamura, Kota Itahashi, Shohei Koyama, Hiroyuki Mizoguchi, Yukihiro Shiraki, Atsushi Enomoto, Fumiharu Ohka, Kazuya Motomura, Yuichiro Tsukada, Masaaki Ito, Yuka Maeda, Ryuzo Ueda, Atsushi Natsume, Ryuta Saito, Hiroyoshi Nishikawa.
      The clinical success of chimeric antigen receptor T cell (CAR T cell) therapy in hematologic malignancies has prompted its application for refractory solid tumors, including glioblastoma (GBM). However, CAR T cell trials against solid tumors have failed to show clinical efficacy thus far. Here, we show that the dysfunction of CAR T cells in GBM is attributed, at least, in part, to glucose deficiency in the tumor microenvironment (TME) driven by the substantial consumption of glucose by cancer cells. Engineering CAR T cells to continuously express glucose transporter 3 (GLUT3), a high-affinity glucose transporter, restored their cytokine production and killing activity. However, although CAR T cells with stable GLUT3 expression induced tumor reduction in a preclinical GBM model, their overactivation led to adverse events and mouse death. In contrast, on-demand GLUT3-expressing CAR T cells, in which GLUT3 transcription was driven by the nuclear translocation of nuclear factor of activated T cells (NFAT) as a consequence of target antigen stimulation, exhibited enhanced metabolic fitness and increased antitumor efficacy, leading to long-lasting tumor control in intracranial human GBM cell xenograft models while preventing adverse events. We propose that on-demand enhancement of metabolic fitness, such as at the time of exposure to tumor antigens, is a concept for boosting the antitumor efficacy of CAR T cells against solid tumors.
    DOI:  https://doi.org/10.1126/scitranslmed.adu3532
  19. Chem Biol Interact. 2026 Apr 14. pii: S0009-2797(26)00192-4. [Epub ahead of print] 112084
    Solute Carrier Transporters in Tumor Metabolism and Tumor Immunity.
    Miaobo Chen, Jie Xu, Heling Ma, Jinlong Qin, Jiajing Cheng, Jia Lv.
      Research on solute carrier (SLC) transporters has become a well-established field, revealing the functional roles of these transmembrane proteins in cancer biology. SLC transporters are transmembrane channel proteins that mostly contain 7 to 12 transmembrane domains and mediate numerous essential physiological functions, including the transportation of metabolites (such as glucose, amino acids, and lipids), signal transduction, immune cell interaction, and the regulation of mitochondrial homeostasis. The expression of SLC transporters shows tissue, disease, and spatiotemporal specificity, and accumulating evidence indicates that SLC transporters are closely associated with pathological conditions, particularly tumor prognosis. Due to the phylogenetic or species conservation, tumor tissue expression specificity, and the ability to functionally target specific pathways of SLC transporters, SLCs have the potential to serve as biomarkers for tumor diagnosis, treatment, and prognosis. SLC transporters play a significant role in tumor metabolism and tumor immunity. They not only influence the metabolism and immune regulation of tumor cells but also affect the metabolism and immune responses of essential components of the tumor microenvironment, such as T cells, natural killer cells, and macrophages. Here, we give a thorough review of the functions that SLCs play in tumor immunity and tumor metabolism, highlighting their impact on immune cell function in the tumor microenvironment and tumor cellular metabolic reprogramming. We also provide an overview of the structure of SLCs, the pharmacology of SLCs, and the current advancements in anticancer therapies targeting SLCs, with particular emphasis on those demonstrating clinical efficacy. In addition to synthesizing recent evidence, this review discusses the challenges in the field of SLC transporters and proposes future research directions.
    Keywords:  cancer immunity; cancer metabolism; pharmacology; solute carrier transporter; structure; targeted therapy
    DOI:  https://doi.org/10.1016/j.cbi.2026.112084
  20. Maedica (Bucur). 2026 Mar;21(1): 97-106
    Complex Features of Tumor-Infiltrating Lymphocytes (TILs) and Stromal Response After Neoadjuvant Breast Chemotherapy.
    Dana Tapoi, Bogdan Adrian Carabas, Mariana Costache.
      Neoadjuvant chemotherapy (NAC) has become a cornerstone in the management of early-stage breast cancer, offering the dual benefits of downstaging tumors to facilitate surgical resection and providing an in vivo assessment of treatment sensitivity (1-3). The tumor microenvironment (TME), comprising a complex network of stromal cells, immune cells and extracellular matrix, plays a pivotal role in modulating therapeutic response (4-6). Within this ecosystem, tumor-infiltrating lymphocytes (TILs) have emerged as a robust biomarker, while stromal response to therapy - characterized by fibrosis, hyalinization and elastosis - reflects host tissue remodeling and may modulate immune function (1, 7-9) along the stromal response to therapy, characterized by features such as fibrosis, hyalinization and elastosis, reflects the host's tissue remodeling processes and may influence immune cell function and tumor behavior (10-13). This study investigates the dynamic interplay between TILs and stromal features in breast cancer following NAC, aiming to elucidate their combined prognostic and predictive significance (9, 14, 15).
    Keywords:  breast cancer; neoadjuvant chemotherapy; tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.26574/maedica.2026.21.1.97
  21. Nat Immunol. 2026 Apr 14.
    Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.
    Qi-Xiang Ma, Ru Zhao, Jiang-Xue Han, Wen-Ying Zhu, Mi-Die Xu, Xiao-Yan Zhang, Guo-Quan Yan, Wen-Yu Wen, Guang-Chun Han, Min Luo, Miao Yin, Jin-Tao Li, Qun-Ying Lei.
      Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context. Here, using clinical samples and genetically engineered mouse tumor models, we showed that tumor-derived BCKAs are secreted actively into the tumor microenvironment (TME) where they reprogram tumor-associated macrophages (TAMs) to promote tumor progression. Through genome-wide CRISPR screening, we identified Notch2 as a direct molecular target of BCKAs. BCKAs activate Notch signaling by binding to and stabilizing cleaved Notch2, functionally reprogramming TAMs and fostering an immunosuppressive TME. Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.
    DOI:  https://doi.org/10.1038/s41590-026-02484-9
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