bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–09–28
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Role of myeloid-derived suppressor cells in bladder cancer and targeted therapeutic strategies.
  2. Immune microenvironment regulation and clinical immunotherapy strategies of metastatic liver cancer.
  3. Cancer Stem Cells Decide the Fate of Cancer Immunotherapy by Remodeling Tumor Microenvironment.
  4. C-C motif glycoprotein ligand 5 (CCL5) and its GPCR CCR5: Macromolecular game-changers in cancer biology.
  5. Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma.
  6. Unveiling the Gut-Pancreas Axis: Microbial Influence on Stemness and Tumor Microenvironment of PDAC.
  7. Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy.
  8. Visualizing cellular interactions: intravital imaging in tumor microenvironment.
  9. Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.
  10. Bruceine D promotes TNBC regression by inhibiting M2-like tumor-associated macrophage polarization induced Wnt3a/β-catenin pathway.
  11. Spatial profiling identifies tumor-associated stroma enrichment and MIF as potential immunotherapy targets in primary Ewing sarcomas.
  12. Bacteria-based immunosuppressive tumor microenvironment reprogramming: a promising dawn in cancer therapy.
  13. M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling.
  14. Apoptosis, ferroptosis, and the autophagy paradox in peritoneal metastasis.
  15. Harnessing the Inflammatory Signature: A Review for Biomarkers in Inflammatory Breast Cancer.
  16. The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment.
  17. Efineptakin alfa (NT-I7) improves overall survival and induces tertiary lymphoid structures in murine lung tumors.
  18. PAI-1 in Skin Malignancies: a Central Regulator of Tumor Progression and Therapeutic Resistance.
  19. SMC4 promotes immune evasion by inhibiting endogenous interferon signaling and upregulating PD-L1 expression in triple negative breast cancer.
  20. ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression.
  21. Oncolytic virotherapy: Sparking durable anti-tumor immunity through microenvironment modulation.
  22. [Neuro-immune interactions in the tumor microenvironment: from mechanisms to precision therapy].
  1. Gene. 2025 Sep 20. pii: S0378-1119(25)00561-X. [Epub ahead of print]970 149772
    Role of myeloid-derived suppressor cells in bladder cancer and targeted therapeutic strategies.
    Sarah Boillat, Vincent Goasmat, Laurent Derré, Sonia Domingos-Pereira.
      
    Keywords:  Bladder cancer (BCa); Combinatorial therapies; Myeloid-derived suppressor cells (MDSCs); Targeted therapeutic strategies; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.gene.2025.149772
  2. Front Immunol. 2025 ;16 1633315
    Immune microenvironment regulation and clinical immunotherapy strategies of metastatic liver cancer.
    Dan Liu, Mingzhu Li, Ying Liang, Fang Xu, Runtian Li, Yang Sun.
      Metastatic liver cancer (MLC) remains a leading cause of cancer-related mortality due to the liver's unique immunotolerant microenvironment and high vascularization. Key mechanisms involve KC-mediated fibronectin deposition, neutrophil extracellular traps (NETs), and MDSC-driven T-cell exhaustion. Clinically, therapeutic strategies targeting the tumor microenvironment (TME) such as CSF1R inhibition, CCR2/CCR5 blockade, and CD40 agonism show promise in preclinical and early-phase trials, especially when combined with immunotherapy. However, challenges remain in overcoming systemic immunosuppression. This review summarizes the dual roles of hepatic immune cells including Kupffer cells (KCs), neutrophils, and myeloid-derived suppressor cells (MDSCs) in either suppressing or promoting metastatic colonization. We elucidate how the liver's immunological balance, governed by innate and adaptive responses, shifts toward immunosuppression during metastasis, fostering a pro-tumor niche. This synthesis of immunological insights underscores the potential of TME-modulating therapies to improve outcomes in MLC.
    Keywords:  Kupffer cells; adaptive immunity; immunotherapy; innate immune cells; metastatic liver cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1633315
  3. Cancer Control. 2025 Jan-Dec;32:32 10732748251381441
    Cancer Stem Cells Decide the Fate of Cancer Immunotherapy by Remodeling Tumor Microenvironment.
    Sourio Chakraborty, Udit Basak, Sumon Mukherjee, Sumoyee Mukherjee, Tanya Das.
      Success of cancer immunotherapy (CIT) is intricately influenced by the tumor microenvironment (TME), a complex ecosystem that encompasses immune cells, stromal elements, and extracellular components. Despite the clinical breakthroughs of immune-checkpoint inhibitors (ICIs), adoptive cell therapies, cancer vaccines, and other immunotherapeutic interventions, many patients fail to respond and eventually die. Emerging evidence points to cancer stem cells (CSCs) as critical drivers of immune evasion, therapy-resistance, and tumor relapse. CSCs modulate the TME by secreting immune-suppressive factors, recruiting regulatory immune cells, and inducing phenotype-switching of anti-tumor TME subsets, thereby creating a protective niche that hinders immune surveillance. Conversely, the TME protects CSCs through hypoxia, altered metabolism, and immuno-suppressive cell populations. This bi-directional crosstalk supports tumor progression and provides resistance to immunotherapeutic strategies mainly by: (i) escaping immune-recognition and inhibiting active T cells via high immune-checkpoint molecule expression, (ii) creating immunosuppressive pro-tumor environment, and (iii) evading immune-mediated apoptosis of CSCs along with therapy-induced enrichment of their pool. Targeting CSCs in concert with reprogramming the TME via CSC-directed agents, metabolic modulators, or combinatorial immunotherapies, therefore, offers a promising avenue to overcome immunotherapy-resistance and achieve durable clinical responses. This review discusses the deeper mechanistic understanding of CSC-TME interactions, in light of designing next-generation immunotherapies with broader efficacy across diverse tumor types.
    Keywords:  cancer immunotherapy; cancer stem cells; immune-suppression; stemness; therapy-resistance; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748251381441
  4. Int J Biol Macromol. 2025 Sep 19. pii: S0141-8130(25)08294-7. [Epub ahead of print]329(Pt 1): 147737
    C-C motif glycoprotein ligand 5 (CCL5) and its GPCR CCR5: Macromolecular game-changers in cancer biology.
    Kosar Ghasemi.
      The C-C motif chemokine ligand 5 (CCL5; also known as RANTES) and its primary G-protein-coupled receptor (GPCR), CCR5, establish complicated signaling pathways, affecting tumor progression through context-dependent immunomodulation and direct contacts with neoplastic cells. This review summarizes current structural and functional evidence linking CCL5's O-linked glycosylation, oligomerization, and glycosaminoglycan interactions to its affinity for CCR5, tissue retention, and gradient formation-molecular attributes that govern leukocyte recruitment, stromal remodeling, angiogenesis, and metastasis. It also discusses mechanistic data showing how CCL5/CCR5 signaling promotes protumorigenic processes, including the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), polarization of tumor-associated macrophages (TAMs), epithelial-mesenchymal transition (EMT), stabilization of programmed cell death-ligand 1 (PD-L1), and therapeutic resistance. In particular, in immune-activating conditions, the recruitment of conventional type 1 dendritic cells (cDC1s), natural killer (NK) cells, and CD8+ T cells is augmented, hence fortifying anticancer immunity. Data from several tumors reveal both detrimental and beneficial effects, dependent on the tumor microenvironment (TME) and therapeutic context. Translational techniques employing CCR5 antagonists such as Maraviroc, GAG-binding modulators, glycoengineered CCL5 variants, delivery systems, and their integration with immune checkpoint inhibitors (ICIs) and targeted therapies are highlighted for their considerable therapeutic promise. Critical research priorities, encompassing single-cell phenotyping, CRISPR-mediated screening of chemokine pathways, and structural-functional mapping, are outlined to facilitate precise modulation of the CCL5/CCR5 axis in targeted cancer therapy. This review addresses structural biology and tumor immunology to identify the CCL5/CCR5 axis as a multifaceted yet promising biological target for innovative cancer therapeutics.
    Keywords:  CCL5; CCR5; Cancer; RANTES; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147737
  5. Trends Mol Med. 2025 Sep 23. pii: S1471-4914(25)00193-5. [Epub ahead of print]
    Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma.
    Amber Wolf, Davide Leardini, Lingzhi Li, Riccardo Masetti, Costas A Lyssiotis, Eveline Barbieri.
      Oncogenic MYCN drives aggressive disease in many cancers including neuroblastoma (NB). Metabolic reprogramming is essential to support cancer cell homeostasis and survival under nutrient- and oxygen-deprived conditions. MYCN directly reprograms many nodes of tumor-intrinsic metabolism, which have significant repercussions on the cells of the tumor microenvironment (TME), resulting in complex intercellular metabolic circuits that contribute to the immunosuppressive microenvironment of NB. These metabolic circuits are also regulated by the organismal and cellular circadian clock and host diet to further impact the TME and NB oncogenesis. This review discusses the mechanisms by which MYCN regulates the metabolic crosstalk between tumor, TME, and host, and provides evidence that therapeutic targeting of MYCN-reprogrammed metabolism can improve patient outcomes.
    Keywords:  MYCN; metabolism; neuroblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2025.08.005
  6. Stem Cells. 2025 Sep 27. pii: sxaf064. [Epub ahead of print]
    Unveiling the Gut-Pancreas Axis: Microbial Influence on Stemness and Tumor Microenvironment of PDAC.
    Kirtana Arikath, Surinder K Batra, Moorthy P Ponnusamy.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and malignant cancer of the pancreas characterized by various genetic mutations and metabolic dysregulations. Stem cells play a critical role in the initiation, progression, and resistance of PDAC due to their plasticity, self-renewal capabilities, and ability to drive tumorigenesis. The gut microbiome, a diverse ecosystem of microorganisms, has a profound influence on systemic health, including the development of cancer. Recent studies have highlighted that the microbiome composition within the tumor can modulate stem cell behavior by shaping the tumor microenvironment (TME), enhancing cellular plasticity, and promoting the stemness properties of PDAC. In this review, we explore the potential crosstalk between the gut microbiome and PDAC stem cells, focusing on how microbiome-derived signals impact stem cell maintenance, inflammation, metastasis, TME modulation, and metabolic reprogramming.
    Keywords:  Cancer; Cancer stem cells; Microenvironment; Pancreas; Stem cell-microenvironment interactions
    DOI:  https://doi.org/10.1093/stmcls/sxaf064
  7. Biochim Biophys Acta Rev Cancer. 2025 Sep 23. pii: S0304-419X(25)00200-8. [Epub ahead of print] 189458
    Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy.
    Zhenting Lu, Midie Xu, Junzhe Tang, Xinyi Wang, Xinxiang Li, Qingguo Li.
      Tumor-associated macrophages (TAMs) are a central component of the tumor microenvironment and exert dual, context-dependent effects on cancer progression. This review synthesizes the mechanisms that govern TAM polarization, their bidirectional crosstalk with tumor and stromal cells, and the consequences of metabolic reprogramming. Molecular and metabolic circuits that shape TAM phenotypes and sustain immune suppression are highlighted, and therapeutic strategies targeting TAM checkpoints, metabolism, and lineage pathways are summarized. To integrate immunometabolism with single-cell and spatial profiling, we introduce a Metabolic-Spatial-Functional Axis that links dominant metabolic programs, anatomic niches, and measurable effector functions. This framework organizes TAM heterogeneity and prioritizes biomarker-guided therapeutic combinations with clear translational readouts. Collectively, these advances support precision approaches that reprogram or constrain TAMs to enhance antitumor immunity and overcome therapeutic resistance.
    Keywords:  Immune evasion; Macrophage polarization; Macrophage-stromal interaction; Metabolic reprogramming; Metabolic-spatial-functional (MSF) axis; Precision immunotherapy; Single-cell RNA sequencing; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189458
  8. Front Immunol. 2025 ;16 1630658
    Visualizing cellular interactions: intravital imaging in tumor microenvironment.
    Shichao Li, Limei Liu, Juanjuan Shan, Cheng Qian.
      The tumor milieu is a dynamic ecosystem where immune cells, stromal cells, and tumor cells interact to influence tumor progression and anti-tumor immunity. Traditional experimental methods, limited to static in vitro or ex vivo analyses at specific time points, cannot fully capture the complexity and dynamic evolution of the tumor microenvironment (TME) in living organisms. Intravital microscopy (IVM), powered by advanced imaging technologies, precise labeling strategies, and optimized experimental approaches, enables real-time visualization of biological structures and cellular interactions within living animals. This review synthesizes findings from IVM-based research, focusing on the dynamic and transient interactions between tumor cells and other cell types, such as normal epithelial cells, immune cells, and stromal cells. It explores the nature of these interactions, their impact on tumor progression, and the outcomes of therapeutic interventions.Overall, we aim to provide a comprehensive resource that highlights the role of IVM in uncovering the dynamic cellular interplay within the TME and its implications for advancing tumor biological research and improving cancer therapies.
    Keywords:  cellular interaction; in vivo imaging; intravital imaging; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1630658
  9. J Adv Res. 2025 Sep 18. pii: S2090-1232(25)00729-5. [Epub ahead of print]
    Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.
    Beibei Ran, Lingjun Xiao, Yan Liu, Chenglin Zhang, Lingkai Kong, Yuxin Zhang, Xiaosong Gu, Chunping Jiang, Junhua Wu.
       BACKGROUND: Tumor-associated macrophages (TAMs) depend on their amino acid metabolism to determine their properties and immune function and play important roles in the tumor microenvironment (TME). Although in previous studies, targeting amino acid metabolism to transform the protumor function of TAMs into antitumor immune function has shown promising application as a tumor therapy, current clinical research is still limited. There is a lack of discussion on the mechanism and treatment strategy for determining tumor progression by controlling amino acid metabolism in TAMs, as does a summary of studies on promoting tumor progression by reshaping amino acid metabolism in TAMs.
    AIM OF REVIEW: This review aims to systematically review and summarize the crosstalk between amino acid metabolism in TAMs and the TME, analyze the determining role of its metabolic network in tumor occurrence and development, and summarize therapies on this basis to help determine the development status and emerging technologies in the field of amino acid metabolism in TAMs for tumor therapy.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review dissects how TAMs exploit amino acid dynamics via transporters, enzymes, and sensors to adopt protumoral phenotypes, depleting critical metabolites and crippling antitumor T-cell responses. We map the immunometabolic crosstalk through which TAMs reshape immunity, highlighting nutrient competition and metabolic byproducts as dual drivers of immune dysfunction. Emerging therapeutic strategies targeting these pathways (IFN-γ-JAK-STAT1 and IL-6/JAK2/STAT3) have been critically evaluated for their potential to reprogram TAMs and reverse immunosuppression. Key challenges, such as TAM heterogeneity, metabolic plasticity, and therapy resistance, are addressed, emphasizing the need for single-cell-resolution mapping of TAM metabolic states to identify context-dependent vulnerabilities. Finally, we advocate for combinatorial approaches that couple metabolic rewiring with immunotherapies, proposing that disrupting amino acid dependencies in TAMs could dismantle the immunosuppressive TME.
    Keywords:  Amino acid; Immunometabolic crosstalk; Immunotherapy; M1-like TAMs; M2-like TAMs; Metabolic crosstalk; Metabolic reprogramming; Therapeutic target; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.jare.2025.09.025
  10. Int Immunopharmacol. 2025 Sep 23. pii: S1567-5769(25)01587-5. [Epub ahead of print]166 115596
    Bruceine D promotes TNBC regression by inhibiting M2-like tumor-associated macrophage polarization induced Wnt3a/β-catenin pathway.
    Yiwen Ma, Di Cao, Xue Han, Zhiqiang Hu, Xiaoyun Ding, Jing Wang.
      Triple-negative breast cancer (TNBC) is distinguished by its marked invasiveness and high recurrence rate, making it the subtype of breast cancer with the most dismal prognosis. Effective treatment modalities for TNBC remains elusive. Tumor-associated macrophages (TAMs) are essential stromal components within the tumor microenvironment, significantly contributing to TNBC progression. Herein, we demonstrated that Bruceine D (BD), a natural quassinoid isolated from Chinese herb Brucea javanica (L.) Merr., diminished the secretion of Wnt3a and downregulated the expression of β-catenin, thereby not only inhibiting the polarization of M2-like macrophages and enhancing the ratio of M1/M2 macrophage but also suppressing M2-like macrophage-promoted proliferation and metastasis of tumor cells. Importantly, BD impeded the polarization of infiltrating M2-like TAMs and inhibited the Wnt3a/β-catenin signaling in tumors, consequently suppressing tumor growth and the formation of metastatic lesions in the lungs and livers of TNBC-bearing mice. This study highlights the promising therapeutic potential of BD in remodeling TAMs as a strategy to address TNBC.
    Keywords:  Bruceine D; Metastasis; Triple-negative breast cancer; Tumor-associated macrophages; Wnt3a/β-catenin
    DOI:  https://doi.org/10.1016/j.intimp.2025.115596
  11. Clin Cancer Res. 2025 Sep 23.
    Spatial profiling identifies tumor-associated stroma enrichment and MIF as potential immunotherapy targets in primary Ewing sarcomas.
    Christopher Kuo, Krinio Giannikou, Nuoya Wang, Mikako Warren, Andrew Goodspeed, Nick Shillingford, Masanori Hayashi, Micha Sam Brickman Raredon, James F Amatruda.
       PURPOSE: The Tumor Microenvironment (TME) has a vital role in cancer survival and progression, and may play roles in drug resistance and immune escape. To date, few studies have detailed the TME of Ewing sarcoma (EwS).
    EXPERIMENTAL DESIGN: We performed spatially resolved transcriptomics of primary treatment-naïve EwS tumor biopsies from patients with or without clinical metastasis, complemented by high-plex spatial proteomic analysis.
    RESULTS: We discovered greater stromal enrichment in localized EwS primary tumors compared to metastasis-associated EwS primary tumors. Through spatial ligand-receptor analysis, we show that the stromal enriched regions harbor unique extracellular matrix related cytokines, immune recruitment and proinflammatory microenvironmental signals, implying EwS stroma may play an anti-tumor role by acting as an immune recruitment center. All EwS tumors expressed pro-tumorigenic MIF-CD74 immune signaling connectivity, suggesting a potential immune-evasive mechanism.
    CONCLUSIONS: In addition to the immune recruitment role of tumor-associated stroma, our findings provide spatial insight into the TME of EwS and provide a rationale for the preclinical investigation of MIF as a potential target for Ewing sarcoma immunotherapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-0635
  12. Microb Cell Fact. 2025 Sep 26. 24(1): 207
    Bacteria-based immunosuppressive tumor microenvironment reprogramming: a promising dawn in cancer therapy.
    Mostafa Akbariqomi, Peyman Kheirandish Zarandi, Azam Abedi, Mehrdad Moosazadeh Moghaddam, Abbas Ali Imani Fooladi.
      Traditional chemotherapy, a prevalent cancer treatment modality, is associated with significant side effects and often leads to treatment failure. Non-specific drug distribution and chemoresistance are the main factors contributing to this failure. Certain distinctive characteristics of the tumor microenvironment (TME), including hypoxia, acidic pH, and increased interstitial fluid pressure, render cancer cells resistant to conventional treatments. Multiple approaches have been devised to enhance the treatment efficiency of neoplasms and overcome chemoresistance. Nowadays, bacteria-based cancer therapy has garnered significant interest in both preclinical and clinical research, owing to its distinctive mechanism and various applications in eliciting host antitumor immunity. Due to their inherent tumor tropism, elevated motility, and capacity for quick colonization in the conducive TME, bacteria are increasingly being considered for targeted tumor treatment. Bacteria, rich in pathogen-associated molecular patterns (PAMPs), can efficiently stimulate immune cells even inside the immunosuppressive TME, boosting the particular immune detection and eradication of tumor cells. Furthermore, outer membrane vesicles (OMVs), cytoplasmic membrane vesicles (CMVs), and their derived physiological components exhibit analogous functionalities to their parental cells. This review article is representative of the latest innovations in bacteria-based immunosuppressive TME reprogramming. Additionally, the article discusses future directions in this research area, drawing on current advances.
    Keywords:  Bacteria-based cancer therapy; Bioengineering bacteria; Immunity; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12934-025-02838-2
  13. Biochim Biophys Acta Mol Basis Dis. 2025 Sep 18. pii: S0925-4439(25)00404-1. [Epub ahead of print] 168056
    M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling.
    Yining Feng, Fei Chen, Chenglong Mu, Luqi Wang, Yuhan Jiang, Dan Liu, Dameng Li, Chen Liang, Yanhua Zhai, Tao Yang, Alan Wells, Amanda M Clark, Liang Wei, Bo Ma.
      Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast cancer progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater breast cancer (BrCa) cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. RNA sequencing also revealed upregulation of the JAK-STAT pathway and elevated phosphorylated STAT3 in these cancer cells. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.
    Keywords:  Breast cancer; Chemoresistance; M1-like macrophages; M2-like macrophages
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168056
  14. Pathol Res Pract. 2025 Sep 15. pii: S0344-0338(25)00418-2. [Epub ahead of print]275 156225
    Apoptosis, ferroptosis, and the autophagy paradox in peritoneal metastasis.
    Jinfeng Qi, Junliang Li, Ruipeng Wang, Yuanyuan Deng.
      Peritoneal metastasis (PM) correlates with a diminished prognosis. Throughout the progression of PM, programmed cell death (PCD) often functions as the body's defense mechanism to eliminate aberrant malignant cells. Paradoxically, PCD within tumor cell populations also holds the potential to exert a pro-cancer effect by modulating the tumor microenvironment (TME). Apoptosis-mediated innate immune cells may orchestrate the pro-cancer TME and could potentially evade cancer therapy. This discussion delineates the impacts of PCD in PM, particularly focusing on apoptosis, ferroptosis, and autophagy, constituting a "double paradox" process. On one hand, PM is restrained through the removal of cancer cells, while on the other hand, it is propelled by the stimulation of repair and regenerative responses in the TME. Furthermore, the interplay of various PCDs such as cell apoptosis, autophagy, and ferroptosis in PM is explored, alongside a summary of PCD-based anticancer strategies. These insights aim to provide a theoretical basis for the prevention and treatment of PM.
    Keywords:  Apoptosis; Autophagy; Ferroptosis; Peritoneal metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.156225
  15. QJM. 2025 Sep 24. pii: hcaf219. [Epub ahead of print]
    Harnessing the Inflammatory Signature: A Review for Biomarkers in Inflammatory Breast Cancer.
    Yingjia Hu, Jian Li, Xinyi Wang, Hongfei Ji, Xingjian Niu.
      Inflammatory breast cancer (IBC) is a highly aggressive breast cancer subtype characterized by rapid progression and poor survival outcomes. In recent years, research on the clinical and molecular features of IBC has brought new hope for its diagnosis and treatment. However, the prognosis of IBC remains extremely poor and novel biomarkers to identify the individual characteristics of patients with IBC are warranted. This review discussed the latest research on IBC biomarkers, especially the unique clinical IBC characterization-related biomarkers, including tumor emboli-related markers and tumor microenvironment (TME)-related markers. Biomarkers based on immune cells in the TME, such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), mast cells, cytokines, and chemokines (e.g., CCL2), may be involved in the development, progression, and treatment resistance of IBC. This study also identified effective biomarkers for IBC and emphasized unique clinical IBC characterization-related biomarkers that may provide strong evidence in IBC diagnosis, prognosis, and therapeutics.
    DOI:  https://doi.org/10.1093/qjmed/hcaf219
  16. Biochim Biophys Acta Rev Cancer. 2025 Sep 22. pii: S0304-419X(25)00189-1. [Epub ahead of print] 189447
    The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment.
    Suman Pakhira, Subhadip Kundu, Sib Sankar Roy.
      Metabolic reprogramming is a defining characteristic of cancer cells as they undergo multistage development. Cancer cells dynamically adjust their metabolism to aid their survival and to retain their malignant traits within the adverse tumour microenvironment (TME). Fatty acid oxidation (FAO) is a major source of cellular bioenergy, making it a key player in driving cancer cell growth. Over the past few years, an accumulating body of literature has shed light on the role of dysregulated FAO in cancer progression. Besides energy production, FAO also plays a protective role by mitigating lipotoxicity-induced cell death and preventing oxidative stress through NADPH production. Moreover, FAO is intricately linked with numerous critical signaling pathways, substantiating its importance as a pivotal metabolic adaptation in cancer cells. In the TME, various intrinsic and extrinsic factors continuously modulate the behaviour of cancer cells, including their metabolic attributes, such as the activation of FAO. Additionally, alterations in FAO within non-cancerous stromal cells also play a critical role in orchestrating the tumor progression. Despite the emerging recognition of FAO's significance in cancer biology, the precise molecular mechanisms underlying its dysregulation within the TME remain poorly understood. Given the pivotal role of FAO in bioenergetically priming the tumor progression, its aberrant regulation has become a focal point of cancer research, offering potential avenues for novel therapeutic strategies. This review provides an overview of recent advances in understanding how different microenvironmental factors modulate FAO to influence tumor progression.
    Keywords:  Fatty acid oxidation; Growth factors; Immune cell metabolism; Metabolic reprogramming; Tumor immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189447
  17. bioRxiv. 2025 Sep 18. pii: 2025.09.15.676444. [Epub ahead of print]
    Efineptakin alfa (NT-I7) improves overall survival and induces tertiary lymphoid structures in murine lung tumors.
    Trang Dinh, Judong Lee, Sidra Islam, Namita Nanda, Dijana Bjelivuk, Dathan Andrews, Jiasen Zhang, Nikita L Mani, Jin Zhou, Alexandra A Wolfarth, Donghoon Choi, Rafi Ahmed, Joseph Skitzki, Deyu Fang, Weihong Guo, Zhenghe Wang, Rebecca C Obeng.
      Tertiary lymphoid structures (TLSs) are emerging as good predictive biomarkers of response to cancer immunotherapy. However, therapeutic strategies to induce these structures are currently limited. We evaluated the therapeutic benefit of efineptakin alfa (NT-I7), a long-acting form of IL-7, and its ability to induce TLSs in a murine lung tumor model. NT-I7 improved overall survival in tumor-bearing mice. It also increased the abundance of T, B, dendritic cells, and stem-like CD8 T cells and promoted the formation of immune aggregates in the tumor microenvironment (TME). Stem-like CD8 T cells were preferentially located in the immune aggregates. Spatial transcriptomic analyses of the TME further demonstrated that the immune aggregates induced by NT-I7 included TLSs with enrichment of Cd274 (PD-L1) transcripts and genes involved in antigen processing and presentation. Upregulation of Cd274 in the TLSs may provide opportunities for synergy between NT-I7 and PD-1-targeted immunotherapy.
    STATEMENT OF SIGNIFICANCE: This study demonstrates the ability of efineptakin alfa (NT-I7) to potentially augment the clinical efficacy of cancer immunotherapy by inducing tertiary lymphoid structures in the tumor microenvironment.
    DOI:  https://doi.org/10.1101/2025.09.15.676444
  18. Curr Treat Options Oncol. 2025 Sep 26.
    PAI-1 in Skin Malignancies: a Central Regulator of Tumor Progression and Therapeutic Resistance.
    Taku Fujimura, Yoshihide Asano.
       OPINION STATEMENT: Plasminogen activator inhibitor-1 (PAI-1) plays a multifaceted and central role in the tumor biology of various skin malignancies. Beyond its classical function in fibrinolysis, PAI-1 contributes to tumor progression by promoting immunosuppression, angiogenesis, cellular senescence, and tissue remodeling. Its expression is particularly elevated in aggressive disease stages across cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), cutaneous angiosarcoma (CAS), and mycosis fungoides (MF), and is associated with poor clinical outcomes. The ability of PAI-1 to induce senescence-associated secretory phenotype (SASP), modulate PD-L1 expression, and recruit tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) suggests a key role in shaping the immunosuppressive tumor microenvironment (TME). This positions PAI-1 as both a potential biomarker for disease progression and a therapeutic target for restoring immune responsiveness, especially in tumors resistant to immune checkpoint inhibitors (ICIs). The PAI-1 inhibitor TM5614 has demonstrated promising activity in early clinical studies, particularly in anti-PD-1-refractory melanoma, and is currently under evaluation in multiple Phase II and III trials. Future strategies should focus on patient stratification using biomarkers such as SASP factors and PAI-1 levels, as well as rational combination therapies targeting interconnected pathways like IL-17/IL-23, AhR, and senescence signaling. Overall, PAI-1 inhibition offers a novel and mechanistically grounded approach to improve outcomes in skin cancers characterized by therapy resistance and an immunosuppressive microenvironment.
    Keywords:  Angiogenesis; Immune checkpoints; PAI-1; SASP; Skin cancer; TME; Tumor progression
    DOI:  https://doi.org/10.1007/s11864-025-01357-x
  19. Int Immunopharmacol. 2025 Sep 20. pii: S1567-5769(25)01571-1. [Epub ahead of print]166 115580
    SMC4 promotes immune evasion by inhibiting endogenous interferon signaling and upregulating PD-L1 expression in triple negative breast cancer.
    Jiayu Zhu, Lei Zhang, Xue Hui, Lingmin Shang, Jianli Ma, Qingyuan Zhang.
       OBJECTIVE: Triple-negative breast cancer (TNBC) is highly invasive and has an inferior prognosis, with the majority of patients deriving limited benefits from immunotherapy. Enhancing the efficacy of immune checkpoint inhibitors (ICIs) remains a formidable challenge for TNBC. Structural maintenance of chromosome 4 (SMC4), a regulator of genomic stability, has been implicated in tumor progression. However, its role in TNBC immune evasion remains unknown.
    METHOD: SMC4 expression and spatial distribution in TNBC were analyzed using bioinformatics, immunohistochemistry, rt-qPCR and western blot. Immunohistochemistry was used to evaluated the association of SMC4 expression with immunotherapy response in advanced TNBC. Stable SMC4-knockdown and overexpression TNBC cell lines were established to assess tumor biology in vitro and in vivo, particularly its regulation of CD8+ T cell function in the tumor microenvironment (TME). Flow cytometry was used to characterize CD8+ T cell phenotypes. Western blot, RT-qPCR, ELISA, molecular docking and immunoprecipitation were used to evaluate the mechanism of SMC4 regulation of immune escape.
    RESULTS: We demonstrated that SMC4 is aberrantly overexpressed in TNBC and correlates with diminished immunotherapeutic response and unfavorable prognosis. Intriguingly, SMC4 drives tumor progression in a CD8+T cell-dependent manner, unveiling its non-canonical role in immune modulation. Mechanistically, SMC4 executes dual immunosuppressive functions hand, SMC4 maintains genomic stability to suppress cGAS-STING-mediated type I interferon production and CD8+ T cells recruitment. In contrast, SMC4 directly impaired CD8+T cell cytotoxicity through STING-independent PD-L1 upregulation. Knockdown SMC4 not only restored tumor immunogenicity, but also potentiated the efficacy of anti-PD-1 therapy in immunocompetent 4T1 murine models.
    CONCLUSION: Our findings establish SMC4 as a dual regulator of immune evasion in TNBC and propose targeting SMC4 as a promising combinatorial strategy to overcome the current limitations in immunotherapy.
    Keywords:  Immune evasion; PD-L1; SMC4; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.intimp.2025.115580
  20. Free Radic Biol Med. 2025 Sep 19. pii: S0891-5849(25)00988-8. [Epub ahead of print]
    ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression.
    Tingting Dang, Yiqing You, Lan Wei, Qian Li, Haoli Sun, MengXin Sun, Xiaolu Li, Shiyu Yang, Tao Zeng, Liang Zhang, Xiran He, Ke Wang, Jiafeng Tang, Yan Zhang.
      The effectiveness of immunotherapy in cervical cancer (CC) is profoundly influenced by the tumor microenvironment (TME), where a high infiltration of M2-type tumor-associated macrophages (TAMs) correlates with poor therapeutic responses. Therefore, understanding the molecular mechanisms driving M2-type TAM polarization and identifying novel therapeutic targets are essential for enhancing immunotherapy outcomes in CC. In this study, ICAT was revealed to be significantly upregulated in CC, correlating with poor prognosis. Mechanistically, ICAT facilitated the nuclear translocation of c-Myc, enhancing ENO1 transcription, thereby promoting glycolytic activity and lactate accumulation in the TME. Tumor-derived lactate induced H3K18 lactylation in TAMs, which in turn activated ARG1 expression, driving M2 polarization and establishing an immunosuppressive microenvironment that supports immune evasion. In summary, this study demonstrates that ICAT, by regulating the c-Myc-ENO1 axis, mediates the interaction between tumor cells and macrophages, thereby reshaping the TME and promoting the migration, invasion, and glycolysis of CC. These findings demonstrate that ICAT represents a potential therapeutic target for the treatment of CC.
    Keywords:  Cervical cancer; ICAT; lactylation; polarization; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.031
  21. Semin Immunol. 2025 Sep 23. pii: S1044-5323(25)00066-1. [Epub ahead of print]80 101994
    Oncolytic virotherapy: Sparking durable anti-tumor immunity through microenvironment modulation.
    Christoph F Kollmann, Nadine van Montfoort, Pierre Cordelier, Jonathan Pol, David Olagnier.
      Oncolytic virotherapy (OVT) is a novel approach to cancer treatment that utilizes viruses to infect and destroy tumor cells selectively. Beyond direct oncolysis, OVT significantly reshapes the tumor microenvironment (TME), activating the adaptive immune system to generate robust and durable anti-tumor immunity. This review examines the diverse mechanisms by which OVT modulates the TME, including physical remodeling, alterations in cellular composition, and the induction of immunogenic cell death, which releases antigens and adjuvants that enhance immune activation. We also explore the synergistic effects of combining OVT with immune checkpoint inhibitors to counteract the immunosuppressive TME. Additionally, recent clinical studies are highlighted, demonstrating the transition of 'cold' tumors to 'hot' tumors and the establishment of systemic tumor control in patients treated with OVT. By enhancing TME immunogenicity, OVT emerges as a potent adjunct to anti-tumor immunotherapies, offering new opportunities to overcome resistance and achieve better therapeutic outcomes.
    Keywords:  Cancer; Clinical trials; Immune checkpoint inhibitors; Oncolytic viruses; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.smim.2025.101994
  22. Zhonghua Wei Chang Wai Ke Za Zhi. 2025 Sep 25. 28(9): 1080-1086
    [Neuro-immune interactions in the tumor microenvironment: from mechanisms to precision therapy].
    Y J Zhang, T P Luo, F L Liu.
      The nervous system, as the core hub of physiological regulation in the human body, plays a key role in the tumor microenvironment through the neuro-immune-tumor axis. Studies have shown that tumor-infiltrating nerve fibers regulate immune cell functions by releasing neurotransmitters, while immune cells can feedback and modulate neuronal activity, forming a dynamic bidirectional interaction network. The emerging field of cancer neuroimmunology focuses on the complex dialogue mechanisms between the nervous and immune systems in the tumor microenvironment. In-depth analysis of the neuro-immune interaction network not only provides new perspectives for understanding tumor immune escape, but also lays the theoretical foundation for developing novel combination therapies targeting the neuro-immune axis, potentially providing breakthrough strategies to overcome resistance to current immunotherapies.
    DOI:  https://doi.org/10.3760/cma.j.cn441530-20250826-00318
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