bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–11–30
seventeen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Immunometabolism in the Tumor Microenvironment: Dual Role in Modulating Anti-Tumor Immunity and Tumor Progression.
  2. Targeting C3a and C5a Signaling-A Game Changer for Cancer Therapy?
  3. Exosome-Mediated Crosstalk Between Cancer Cells and Tumor Microenvironment.
  4. Macrophages and neutrophils in ovarian cancer microenvironment.
  5. Bidirectional regulation of lipid metabolism and the tumor microenvironment: new perspectives from mechanism to therapy.
  6. IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer.
  7. p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer.
  8. Lipid metabolic reprogramming in the tumor microenvironment and its mechanistic role in immunosuppressive cells.
  9. The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.
  10. Cellular senescence in the innervated niche modulates cancer-associated pain: an emerging therapeutic target?
  11. Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
  12. Diallyl Trisulfide Suppresses Tumor-Associated Macrophage M2-Like Polarization and Recruitment and Improves the Tumor Microenvironment Through Blocking CCL5/STAT3 Signaling Pathway Against Lung Cancer.
  13. Vimentin in the tumor microenvironment: orchestrating invasion, immunity, and metabolism.
  14. Nerve Adaptations in the Tumor Microenvironment.
  15. Azvudine remodels the local immunosuppressive microenvironment and exhibits sustained anti-tumor effects in combination with anti-PD-1 therapies.
  16. Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
  17. Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.
  1. Asian Pac J Cancer Prev. 2025 Nov 20. pii: 91914. [Epub ahead of print]26(11): 3881-3893
    Immunometabolism in the Tumor Microenvironment: Dual Role in Modulating Anti-Tumor Immunity and Tumor Progression.
    Casterland Marbaniang, Lakhon Kma, Rajeshwar Nath Sharan.
      Understanding the tumor microenvironment (TME) requires a comprehensive exploration of the interactions between tumor cells and various stromal and immune cells, as these interactions significantly influence tumor growth and treatment response. Immunometabolism, which examines the relationship between immune cell metabolic processes and their behaviour, has become crucial in determining the effectiveness of anti-tumor immune responses. This review explores the intricate relationship between immunometabolism and TME, highlighting how metabolic changes in immune cells can either enhance or impair their capacity to fight cancer. It specifically investigates the metabolic reprogramming of T cells, macrophages, and dendritic cells within the TME and how these alterations affect their anti-tumor roles. The review also examines how tumors utilise metabolic pathways to establish an immunosuppressive environment that fosters tumor growth. Understanding these processes reveals potential therapeutic targets in immunometabolism to improve cancer treatment outcomes. By emphasising the dual role of immunometabolism in both aiding and inhibiting the immune response to cancer, this review underscores the necessity of integrating metabolic strategies into cancer immunotherapy research, which may lead to novel treatments that maximise the immune system's ability to combat cancer.
    Keywords:  Immunometabolism; TME; Tumor; immune cells; immunosuppressive environment
    DOI:  https://doi.org/10.31557/APJCP.2025.26.11.3881
  2. Biology (Basel). 2025 Oct 25. pii: 1491. [Epub ahead of print]14(11):
    Targeting C3a and C5a Signaling-A Game Changer for Cancer Therapy?
    Hunter Hudgins, Valeria Molina, Stanley Wiernicki, Kenneth Okwuegbe, Xiaodong Feng, Hongbin Wang.
      Emerging evidence reveals a significant shift in understanding the complement system's role in cancer, where activation of a complement within the tumor microenvironment (TME) fuels tumor growth and metastasis instead of suppressing it. Research highlights C3a and C5a anaphylatoxins as key drivers of cancer progression, showing that the blockade of their signaling pathways can inhibit tumor growth and metastasis. By interacting with immune cells in the TME, including tumor-associated macrophages (TAMs), T cells, and myeloid-derived suppressor cells, C3a and C5a promote immunosuppression, thereby driving cancer cell proliferation, angiogenesis, and metastasis. However, conflicting findings persist, despite growing evidence supporting the role of C3a and C5a in tumor progression and the potential therapeutic benefits of targeting pathological complement activation. This paper presents a systematic review of studies examining the activation of the complement system and the role of the C3a and C5a signaling pathways in the TME, focusing on their effects on tumor progression, their interactions with TME components, and the potential for targeting these signaling pathways to boost anti-tumor immune responses.
    Keywords:  C3a/C3aR signaling; C5a/C5aR signaling; cancer; complement; immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/biology14111491
  3. Cells. 2025 Nov 08. pii: 1750. [Epub ahead of print]14(22):
    Exosome-Mediated Crosstalk Between Cancer Cells and Tumor Microenvironment.
    Sara H Saad, Alex Kashanchi, Mohammad Asad Zadeh, Anastasia Williams, Elena V Batrakova.
      Exosomes are extracellular vesicles that play a central role in mediating intercellular communication within the tumor microenvironment (TME). Cancer-derived exosomes carry proteins, nucleic acids, and lipids that reshape the phenotype and function of surrounding stromal and immune cells, thereby promoting tumor progression, angiogenesis, metastasis, and resistance to therapy. At the same time, exosomes derived from TME components, including macrophages, dendritic cells, B cells, T cells, fibroblasts, neutrophils, and NK cells, reciprocally influence tumor growth and immune evasion. These bidirectional interactions highlight exosomes as both drivers of tumor progression and regulators of antitumor immunity. In this review, we synthesize current evidence on the diverse mechanisms by which exosomes reprogram immune and stromal cells, with a focus on their dual roles in cancer biology. We also discuss emerging therapeutic strategies to inhibit exosome biogenesis, release, and function, underscoring their translational potential as novel targets for cancer diagnosis and treatment.
    Keywords:  B cells; cancer progression; dendritic cells; exosomes; extracellular vesicles (EVs); immune modulation; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/cells14221750
  4. Front Immunol. 2025 ;16 1677441
    Macrophages and neutrophils in ovarian cancer microenvironment.
    Kuang-Chao Cheng, Yu-Hsin Lin, Dao-Sian Wu, Ie-Ming Shih, Tian-Li Wang.
      Ovarian cancer (OC) remains one of the most aggressive gynecological malignancies, with a five-year survival rate below 45% despite the recent advances in the introduction of targeted therapy. Moreover, immunotherapy, such as immune checkpoint inhibitors, does not improve the survival of OC patients. Lack of sufficient knowledge in understanding the complexity of the tumor microenvironment likely confers the treatment ineffectiveness. Recently, tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have garnered research attention as they shape the tumor immune microenvironment, which plays a crucial role in disease progression and treatment response. This article reviews the complex roles of these innate immune cells in OC progression. TAMs represent a significant component of the immune infiltrate in OC, exhibiting considerable functional plasticity and can shift between anti-tumoral (M1) and pro-tumoral (M2) phenotypes. M2-like TAMs typically predominate in the tumor microenvironment, which aids in the development of immune suppression and disease progression. They also contribute to chemoresistance and metastasis; hence, their presence in tumors is associated with a worse prognosis. TANs, like TAMs, exhibit N1/N2 polarization and influence tumor progression through the formation of neutrophil extracellular traps. Understanding the biological interactions between various immune cells and cancer cells may offer new therapeutic opportunities. This review sheds light on the dynamic ecological transformation of the OC tumor microenvironment and highlights the potential of targeting TAM/TAN-mediated processes to improve OC treatment outcomes.
    Keywords:  immunotherapy; ovarian cancer; tumor microenvironment; tumor-associated macrophages (TAMs); tumor-associated neutrophils (TANs)
    DOI:  https://doi.org/10.3389/fimmu.2025.1677441
  5. Front Immunol. 2025 ;16 1696102
    Bidirectional regulation of lipid metabolism and the tumor microenvironment: new perspectives from mechanism to therapy.
    Kaixin Shi, Bing Pan, Ruixin Zheng, Kaiyi Liu, Jincheng Song, Xiaobo Wang, Li Li.
      The role of lipid metabolism in cancer and immune regulation has received significant attention in recent years. Reprogramming of lipid metabolism is one of the key hallmarks of cancer and plays a critical role in cancer progression by supporting the rapid proliferation, survival, and metastasis of tumor cells. Importantly, beyond its well-established functions in cancer cells, lipid metabolism dynamically regulates the functions of various immune cells within the TME (e.g., T cells, natural killer cells, macrophages), thereby molding antitumor immune responses. This review combines the contemporary awareness of the reciprocal interactions between lipid metabolism and the TME. We start with a simple overview of key lipid metabolic pathways in cancer cells, followed by an in-depth exploration of the way lipid uptake, synthesis, and oxidation influence the fate and role of tumor-infiltrating immune. We also appraise the translational potential of targeting lipid metabolism and propose that combining inhibitors of key metabolic enzymes, for example fatty acid synthase or acetyl-CoA carboxylase, with immunotherapy can not only effectively alleviate immunosuppression but also overcome immunosuppression. Finally, we spotlight the remaining knowledge gaps and put forward future research priorities and potential. Intervening in lipid metabolic interactions represents a promising prospect for developing the novel cancer treatment strategies.
    Keywords:  cancer; immune response; lipid; lipid metabolism; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1696102
  6. bioRxiv. 2025 Oct 15. pii: 2025.10.14.682312. [Epub ahead of print]
    IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer.
    Yabing Nan, Sophie O'keefe, Xiadi He, Qingyu Luo, Xiaowei Wu, Jing Ni, Yutian Zou, Jerryd Marcus Meade, Yutong Li, Renlei Ji, Anwaruddin Mohammad, Pankaj Kumar, Qiwei Wang, Jean J Zhao.
      Tumor-associated macrophages (TAMs) are major contributors to immunosuppression and therapeutic resistance, including resistance to PARP inhibitors (PARPi) in BRCA1-deficient breast cancer. However, the mechanisms underlying TAM-mediated PARPi resistance remain unclear. Here, we demonstrate that TAM-derived glutathione (GSH) impairs the efficacy of PARPi by protecting tumor cells from DNA damage and ferroptosis while suppressing STING-mediated immune activation. Mechanistically, STAT5-driven upregulation of the IRG1/itaconate axis in TAMs rewires mitochondrial metabolism and activates NRF2-dependent GSH biosynthesis. GSH is subsequently released into the tumor microenvironment, where it is taken up by tumor cells, protecting them from PARPi-induced cytotoxicity and dampening immune responses. Pharmacological inhibition of IRG1 reverses these effects, restoring PARPi sensitivity and enhancing anti-tumor immunity in BRCA1-deficient tumor models. Collectively, these findings uncover a TAM-specific immunometabolic program that limits PARPi efficacy and highlight the IRG1/NRF2/GSH axis as a promising therapeutic target to improve treatment outcomes in BRCA1-associated breast cancer.
    DOI:  https://doi.org/10.1101/2025.10.14.682312
  7. Res Sq. 2025 Oct 29. pii: rs.3.rs-7151795. [Epub ahead of print]
    p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer.
    Priyanka Rajan, Robert Zollo, Yanqi Guo, Mohammed Alruwaili, Justin Zonneville, Mackenzie Lieberman, Brian Morreale, Caitlin James, Mark Long, Scott H Olejniczak, Joseph Barbi, Scott I Abrams, Andrei V Bakin.
      Metastatic breast cancer (MBC) is a life-threatening disease with limited therapeutic options. The immune suppressive tumor microenvironment (TME) limits the potency of the antitumor immune response and facilitates disease progression and metastasis. Our current study demonstrates that p38α is a druggable target in the TME that regulates the outcome of the immune-tumor interaction. The study revealed that systemic blockade of p38α reduces metastasis, and this anti-metastatic response is negated by depletion of CD8 + T cells. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38α by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8 + T cell phenotype. Immunophenotyping analyses demonstrated that p38 blockade reduced the expression of multiple inhibitory receptors on CD8 + T cells (i.e., PD-1, LAG-3, CTLA-4), indicating a reversal of immune exhaustion and enhanced immune activation systemically and in the TME. In contrast, p38 blockade did not exhibit inhibitory effects on T cells in proliferation assays in vitro and did not affect the proportion of regulatory T cells in vivo . The major negative impact of p38 blockade in vivo was on the myeloid populations, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Further, tumor p38α activity was required for the expression of cytokines/chemokines and tumor-derived exosomes with high chemotactic capacity for myeloid cells. Altogether, this study highlights a previously unrecognized the p38α-driven pathway that promotes an immune suppressive TME and metastasis, and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.
    DOI:  https://doi.org/10.21203/rs.3.rs-7151795/v1
  8. Front Immunol. 2025 ;16 1728354
    Lipid metabolic reprogramming in the tumor microenvironment and its mechanistic role in immunosuppressive cells.
    Wenbo Liu, Ziyi Wang, Zehui Li, Shijie Li, Xialing Shi, Yan Xu, Jin Wang.
      
    Keywords:  immunometabolic; lipid metabolic; metabolic reprogramming; myeloid-derived suppressor cells; regulatory T cells; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1728354
  9. Front Immunol. 2025 ;16 1696113
    The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.
    Dong-Xu Liao, Xiang An, Gui-Xiang Huang, Tong-Ling Yuan.
      Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, characterized by high incidence and mortality rates. Despite advancements in surgical and systemic therapies, the prognosis remains poor due to the asymptomatic nature of early-stage HCC. Metabolic reprogramming in HCC cells usually creates an immunosuppressive tumor microenvironment (TME), thereby impeding T cell-mediated antitumor immunity. This review focuses on the metabolic reprogramming patterns in HCC, their impact on T cell function, and the potential of metabolic-immune targeted combination therapies. We emphasize that nutrient competition and the accumulation of inhibitory metabolites are key mechanisms underlying T cell suppression in the TME. This review provides an update on the complex metabolic-immune interactions and helps to identify new therapeutic targets to improve the efficacy of immunotherapy for HCC.
    Keywords:  T cell-mediated antitumor immunity; hepatocellular carcinoma (HCC); metabolic reprogramming; metabolic-immune targeted combination therapies; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1696113
  10. Front Immunol. 2025 ;16 1694567
    Cellular senescence in the innervated niche modulates cancer-associated pain: an emerging therapeutic target?
    Fabrizio Antonangeli, Edoardo Arcuri, Angela Santoni.
      Crosstalk between cancer cells and the nervous system establishes the so-called "innervated niche". This component of the tumor microenvironment (TME) influences tumor progression and variably regulates the genesis and maintenance of cancer-related pain. Senescence is a cellular stress response emerging as a hallmark of cancer and aging. Through the inflammatory secretome referred to as the senescence-associated secretory phenotype (SASP), senescent cells execute immunomodulation and tissue remodeling, participating in many physio-pathological processes. As inflammation is a key determinant of the TME as well as of neuropathies, in this review article we try to outline the possible role of senescence in the innervated niche. We argue that senescence can contribute to neuroinflammation, which is nowadays recognized as the initial factor triggering both cancer and non-cancer pain, by boosting local inflammation in the TME. At the same time, senescent cells can become targetable elements of the innervated niche to control cancer pain. We describe how the immune system supports the resolution of pain, and we suggest the possibility of harnessing natural killer (NK) cells, the prototype of innate immunity lymphocytes, for therapeutic approaches aimed at pain relief.
    Keywords:  NK cell; SASP; cancer; neuroinflammation; neuropathy; pain; senescence; senolysis
    DOI:  https://doi.org/10.3389/fimmu.2025.1694567
  11. bioRxiv. 2025 Nov 13. pii: 2025.11.11.687895. [Epub ahead of print]
    Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
    Azusa Terasaki, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Keshav Bhatnagar, Cara C Rada, Vishnu Shankar, Courtney Kernick, Mahnoor Mahmood, Lukas Wiggers, Viviana R Rodrigues, Payam A Gammage, Theodore Roth, Jeffrey D Axelrod, Edgar Engleman, Bo Li, Derick Okwan-Duodu.
      Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.
    HIGHLIGHTS: Tumor cells regulate their ecosystem by redistributing mitochondriaRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cellsMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CSMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem.
    DOI:  https://doi.org/10.1101/2025.11.11.687895
  12. Phytother Res. 2025 Nov 26.
    Diallyl Trisulfide Suppresses Tumor-Associated Macrophage M2-Like Polarization and Recruitment and Improves the Tumor Microenvironment Through Blocking CCL5/STAT3 Signaling Pathway Against Lung Cancer.
    Chunfeng Xie, Juan Yin, Jianyun Zhu.
      Diallyl trisulfide (DATS) is a promising small molecule phytochemical derived from allium vegetables with antitumor potential. Tumor-associated macrophages (TAMs) are the most abundant tumor-infiltrating immune cells within the lung tumor microenvironment (TME), and significantly promote immunosuppression and tumor progression. However, the effect of DATS on TAM phenotype and function and its role in tumor immunity remain unexplored. Lewis lung cancer (LLC) mouse model was established to observe the effects of DATS on tumor growth, populations of TAMs and T cells in vivo. Meanwhile, a lung cancer cell/macrophage co-culture system was used to evaluate the effects of DATS on TAM phenotype and function in vitro. A transcriptome database was used to further explore the underlying mechanisms of DATS in TAMs. Our results showed that DATS worked as a modulator of TAM phenotype and function. DATS inhibited TAMs' polarization toward the immunosuppressive M2 phenotype and promoted TAMs' polarization to the M1 phenotype in vivo and in vitro. Mechanistically, we observed a significant decrease in CCL5 levels and a negative enrichment of the JAK-STAT3 signaling pathway in DATS-treated TAMs. Further investigation revealed that DATS hindered the immunosuppressive phenotype and migration ability of TAMs through the CCL5/STAT3/PD-L1 axis. Additionally, DATS reshaped the lung TME and enhanced antitumor immunity by increasing the numbers of CD4+ and CD8+ T cells and decreasing regulatory T cells (Tregs). In summary, our results illustrate that DATS enhances antitumor immunity and suppresses lung cancer progression by regulating TAM phenotype and function via blocking the CCL5/STAT3/PD-L1 pathway. These findings provide a new mechanism of DATS against lung cancer, suggesting the potential clinical value of DATS in lung cancer treatment.
    Keywords:  CCL5; STAT3; diallyl trisulfide; lung cancer; tumor associated macrophages
    DOI:  https://doi.org/10.1002/ptr.70138
  13. Eur J Cell Biol. 2025 Nov 21. pii: S0171-9335(25)00048-2. [Epub ahead of print]104(4): 151523
    Vimentin in the tumor microenvironment: orchestrating invasion, immunity, and metabolism.
    Sepideh Parvanian, John E Eriksson.
      Vimentin, a type III intermediate filament protein, has gained recognition as a multifunctional regulator within the tumor microenvironment (TME). While traditionally considered a hallmark of epithelial-to-mesenchymal transition (EMT), vimentin is increasingly understood as a structural and signaling hub essential for the functional complexity of mesoderm-derived and EMT-transitioned cells. It bridges cytoskeletal architecture with key signaling networks, linking cellular plasticity to mechanotransduction, immune modulation, and metabolic regulation. This unique versatility underlies vimentin's essential role in supporting the migratory, remodeling, and adaptive behaviors required in contexts such as wound healing, inflammation, and tissue remodeling-capabilities that cancer cells have co-opted to their advantage. Indeed, vimentin's pervasive expression across aggressive cancers reflects its ability to scaffold and coordinate the cytoskeletal and signaling rewiring needed for malignancy. This review provides an integrated overview of vimentin's diverse roles in the TME, emphasizing its contributions to tumor invasiveness, immune regulation, and metabolic adaptation. We conclude by discussing how these insights may inform the development of vimentin-centered strategies to improve therapeutic outcomes in cancer.
    Keywords:  Cancer Invasion; Cancer Therapy; EMT; Immunity; Intermediate Filaments; Metabolism; Tumor Microenvironment; Vimentin
    DOI:  https://doi.org/10.1016/j.ejcb.2025.151523
  14. Cell Biochem Funct. 2025 Dec;43(12): e70147
    Nerve Adaptations in the Tumor Microenvironment.
    Aditi Swamy, Karishma Ravikumar, Merlin Pious, Ahina Job, Denny John, Sahadev A Shankarappa.
      The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal components, immune infiltrates, and neural elements. The presence and growth of nerves within or in close association with tumor tissue, a phenomenon known as tumor innervation, has long been observed. However, recent evidence supports a more active role for peripheral nerves in regulating cancer growth, metastasis, and therapeutic resistance. What remains underappreciated is the reciprocal influence of cancer cells on the nervous system. Accumulating data indicate that cancer cells remodel adjacent nerve terminals, triggering structural, neurochemical, bioelectrical, and transcriptional changes in a tumour-type-specific manner. These adaptations resemble pathways observed in nerve regeneration and suggest a tightly regulated, bidirectional signaling axis between cancer and nerves. In this review, we systematically consolidate emerging literature describing these nerve adaptations and categorize them across multiple levels, from morphological remodeling and neurotransmitter shifts to bioelectrical signaling and neuroimmune crosstalk. We highlight the central role of the tumor secretome in mediating nerve-cancer communication and emphasize how neural elements actively shape tumor behavior. By consolidating and critically examining findings across diverse cancer models and experimental systems, this review provides a mechanistic framework for understanding neural remodeling in cancer and identifies key areas for future investigation, including the potential of targeting nerve-tumor interactions as a therapeutic strategy.
    Keywords:  cancer progression; cancer–neuron crosstalk; neural remodeling; perineural invasion; tumor innervation
    DOI:  https://doi.org/10.1002/cbf.70147
  15. Front Med. 2025 Nov 24.
    Azvudine remodels the local immunosuppressive microenvironment and exhibits sustained anti-tumor effects in combination with anti-PD-1 therapies.
    Limin Jia, Zhaoyang Wang, Jinfa Du, Zhigang Ren, Jiandong Jiang, Pan Li.
      The immunosuppressive tumor microenvironment (TME) undermines the efficacy of many cancer therapies. This study investigated the immunomodulatory and anti-tumor activity of Azvudine (FNC), alone or in combination with anti-PD-1 blockade. We established syngeneic tumor models in immunocompetent mice. Single-cell RNA sequencing, flow cytometry, and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration. FNC demonstrated dose- and time-dependent tumor inhibition. It significantly expanded memory T cells, natural killer (NK) cells, and CD8+ cytotoxic T lymphocytes, while reducing the abundance of myeloid-derived suppressor cells (MDSCs). Flow cytometry confirmed these immunological shifts, showing enhanced infiltration of effector immune cells within the TME. Moreover, FNC induced hallmark features of immunogenic cell death (ICD), including the release of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1) and calreticulin. When combined with anti-PD-1 therapy, FNC produced a synergistic anti-tumor effect, leading to durable tumor remission in all treated mice. FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity, offering a promising strategy to augment existing immunotherapies. Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.
    Keywords:  Azvudine; anti-PD-1 therapy; immunogenic cell death; immunosuppressive microenvironment; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.1007/s11684-025-1164-0
  16. bioRxiv. 2025 Oct 23. pii: 2025.10.22.684010. [Epub ahead of print]
    Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
    Wen-Hsuan Yang, Olivia T Stamatatos, Evdokia Michalopoulou, Ava Sann, Paolo Cifani, Linda Van Aelst, Justin R Cross, Tse-Luen Wee, Michael J Lukey.
      Avid nutrient consumption is a metabolic hallmark of cancer and leads to regional depletion of key metabolites within the tumor microenvironment (TME). Cancer cells consequently employ diverse strategies to acquire the fuels needed for growth, including bulk uptake of the extracellular medium by macropinocytosis. Here, we show that breast and pancreatic cancer cells macropinocytically internalize extracellular DNA (exDNA), an abundant component of the TME, and deliver it to lysosomes for degradation. This provides a supply of nucleotides that sustains growth when de novo biosynthesis is impaired by glutamine restriction or pharmacological blockade. Mechanistically, this process is dependent on the non-redundant lysosomal equilibrative nucleoside transporter SLC29A3 (ENT3), which mediates the export of nucleosides from the lysosomal lumen into the cytosol. Accordingly, genetic ablation of SLC29A3 or pharmacological disruption of lysosomal function prevents exDNA scavenging and potently sensitizes breast tumors to antimetabolite chemotherapy in vivo . These findings reveal a previously unrecognized nutrient acquisition pathway through which cancer cells recycle exDNA into metabolic building blocks and highlight SLC29A3 as a mediator of metabolic flexibility and a potential target to improve chemotherapy response.
    DOI:  https://doi.org/10.1101/2025.10.22.684010
  17. Int J Biol Sci. 2025 ;21(15): 6952-6977
    Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.
    Jinglei Zhang, Zhuohuan Chu, Jiawen Li, Lu Xie, Cong Ding, Zihui An, Xiang Wang, Hangbin Jin, Xiaofeng Zhang, Qiang Liu, Jianfeng Yang.
      Biliary and pancreatic malignant tumors refer to biliary tract carcinoma (BTC) and pancreatic cancer (PC), among which BTC mainly includes cholangiocarcinoma (CCA) and gallbladder cancer (GBC), and their prognosis is poor because of the lack of effective early diagnostic methods. Although surgical resection is the preferred method for a cure, treatment options are limited for patients with advanced tumors. Therefore, the exploration of other new treatment methods is urgently needed. Currently, metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. As an indispensable part of metabolic reprogramming in tumor cells, amino acid (AA) metabolic reprogramming provides an energy source for tumor cells and participates in regulating the tumor microenvironment (TME). Moreover, as important intrinsic myeloid cells, macrophages play indispensable physiological roles in malignant tumor progression. In the TME, tumor cells can not only induce peripheral immune tolerance by releasing extracellular signals but also compete with tumor-associated macrophages (TAMs) for AAs and release the resulting downstream metabolites into the TME, directly targeting and damaging immune cells and influencing macrophage polarization. Consequently, a more profound understanding of the function of AA metabolic reprogramming in biliopancreatic malignancies and their associated macrophage polarization holds the potential to facilitate the development of effective strategies for early diagnosis, prognostic assessment and targeted therapy in patients with biliopancreatic malignancies. In this paper, we review the impact of AA metabolic reprogramming on the occurrence and development of biliary and pancreatic malignant tumors, summarize the relevant mechanisms of AA metabolic reprogramming on the polarization of TAMs, and provide new therapeutic targets for AA metabolic therapies and immunotherapies for biliary and pancreatic malignant tumors.
    Keywords:  amino acid metabolism; cholangiocarcinoma; metabolic reprogramming; pancreatic cancer; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.122325
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