bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–09–14
twenty papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Immunosuppressive tumor microenvironment and advance in immunotherapy in melanoma bone metastasis.
  2. Cancer-associated fibroblast-mediated immune evasion: molecular mechanisms of stromal-immune crosstalk in the tumor microenvironment.
  3. [The Role of Tumor-Associated Macrophages in Anti-PD-1/PD-L1 Immunotherapy for Lymphoma--Review].
  4. Advances in Tumor Microenvironment and Immunotherapeutic Strategies for Hepatocellular Carcinoma.
  5. The Role of Tumor Microenvironment in Triple-Negative Breast Cancer and Its Therapeutic Targeting.
  6. Lysine-Leucine-Rich Frog Skin Antimicrobial Peptides Inhibit Breast Cancer Metastasis by Reprogramming Tumor-Associated Macrophage Polarization.
  7. TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
  8. The Role of Recruited Adipose Stromal Cells and Their Fibroblastic Differentiation in Cancer.
  9. UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer.
  10. Cancer-Associated Fibroblasts in Solid Tumors and Sarcomas: Heterogeneity, Function, and Therapeutic Implications.
  11. Progress in targeting tumor-associated macrophages in cancer immunotherapy.
  12. Targeting TAMs & CAFs in melanoma: New approaches to tumor microenvironment therapy.
  13. Ferroptosis in the tumor microenvironment: mechanisms, advances, and therapeutic perspectives.
  14. Host and microbiome lipid metabolism in colorectal cancer development and therapy.
  15. Integrating Metabolic Modulation and Nanomedicine for Cancer Immunotherapy.
  16. Cellular Senescence and Immunosenescence in Melanoma: Insights From the Tumor Microenvironment.
  17. Immunotherapy resistance in triple-negative breast cancer: Molecular mechanisms, tumor microenvironment, and therapeutic implications.
  18. Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors.
  19. Lactate modulates the function of myeloid-derived suppressor cells via Ten-Eleven-Translocation-2-mediated demethylation of glucocorticoid-inducible kinase 1 in lung cancer model.
  20. Targeting collagen in "armored and cold" tumors: Overcoming barriers to cancer therapy.
  1. Front Immunol. 2025 ;16 1608215
    Immunosuppressive tumor microenvironment and advance in immunotherapy in melanoma bone metastasis.
    Yiqun Ma, Lin Zhang, Weimin Liu.
      Melanoma frequently develops bone metastases, leading to skeletal-related events and poor survival. The tumor microenvironment (TME) plays a pivotal role in melanoma progression, bone metastasis, and immunotherapy resistance. Key immunosuppressive cells including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs) promote immune evasion and osteolytic bone destruction via RANKL-dependent and -independent mechanisms. Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 and anti-PD-1/PD-L1 therapies, have revolutionized melanoma treatment, yet resistance remains common due to TME immunosuppression. Emerging strategies, such as combination therapies, aim to enhance efficacy by reshaping the TME. This review synthesizes current knowledge on TME-driven immunosuppression, bone metastasis mechanisms, and immunotherapeutic advancements, offering insights into overcoming resistance and improving patient outcomes.
    Keywords:  bone metastasis; immune checkpoint inhibitors; immunotherapy; melanoma; osteoclasts; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1608215
  2. Front Immunol. 2025 ;16 1617662
    Cancer-associated fibroblast-mediated immune evasion: molecular mechanisms of stromal-immune crosstalk in the tumor microenvironment.
    Junling Luo, Xuehua Xiang, Guangyuan Gong, Lang Jiang.
      The tumor microenvironment (TME) is a complex ecosystem and cancer-associated fibroblasts (CAFs) are critical drivers of the immunosuppressive TME. The dynamic interactions between CAFs and immune cells play a crucial role in tumor progression and immune evasion. This review systematically investigates the interactions between CAFs and different immune cells and elaborates on the molecular mechanisms of CAF-mediated immune suppression, with a focus on their multifaceted interactions with various immune cell populations. The present study discusses how CAFs utilize cytokine networks, metabolic reprogramming and immune checkpoint regulation to establish an immunosuppressive TME. Clinical translation should prioritize FAP-directed therapies alongside αPD-1 to concurrently target CAF-immune crosstalk and metabolic competition in the TME.
    Keywords:  CAFs; cancer-associated fibroblasts; immune cells; immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1617662
  3. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Aug;33(4): 1217-1221
    [The Role of Tumor-Associated Macrophages in Anti-PD-1/PD-L1 Immunotherapy for Lymphoma--Review].
    Xing-Hui Jiang, Yi-Jian Chen.
      Lymphoma is a malignant tumor originating from lymphatic tissue, which can be roughly divided into two types: Hodgkin's lymphoma and non-Hodgkin's lymphoma. It has the characteristics of high recurrence rate, high mortality rate, and short survival time. Tumor cells in lymphoma form a tumor microenvironment (TME) that inhibits host anti-tumor immunity with surrounding immune cells, while tumor-associated macrophages (TAMs) are a key cell in TME. TAMs promote immune evasion of tumor cells in some ways by producing various cytokines and/or abnormal expression of immune checkpoint molecules. Programmed death receptor-1 (PD-1) and its ligand 1 (PD-L1) are important negative regulatory factors for immune cell activation. Recent studies have shown that anti-PD-1/PD-L1 therapy represents a new strategy for lymphoma immunotherapy. This article will focus on the role and expression of TAMs and PD-1/PD-L1 in lymphoma, and explore the efficacy of anti-PD-1/PD-L1 immunotherapy in different types of lymphoma.
    Keywords:  lymphoma; tumor-associated macrophage; PD-1/PD-L1; tumor microenvironment
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.04.043
  4. Oncol Res. 2025 ;33(9): 2309-2329
    Advances in Tumor Microenvironment and Immunotherapeutic Strategies for Hepatocellular Carcinoma.
    Jiahao Xue, Jingchang Zhang, Gang Chen, Liucui Chen, Xinjun Lu.
      Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, largely driven by an immunosuppressive tumor microenvironment (TME) that facilitates tumor growth, immune escape, and resistance to therapy. Although immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses, their clinical benefit as monotherapy remains suboptimal. This limitation is primarily attributed to immunosuppressive components within the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). To address these challenges, combination strategies have been explored, such as dual checkpoint blockade targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions. These approaches have shown encouraging potential in enhancing immune efficacy. This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC, emphasizing how combination regimens may overcome immune resistance. Furthermore, we discuss the remaining hurdles, including therapeutic resistance and immune-related adverse events, and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.
    Keywords:  Hepatocellular carcinoma (HCC); combination therapy; immune checkpoint inhibitors (ICIs); immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.32604/or.2025.063719
  5. Cells. 2025 Aug 30. pii: 1353. [Epub ahead of print]14(17):
    The Role of Tumor Microenvironment in Triple-Negative Breast Cancer and Its Therapeutic Targeting.
    Ana Vuletic, Katarina Mirjacic Martinovic, Vladimir Jurisic.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by rapid proliferation and infiltration of immune cells into tumor microenvironment (TME). The treatment of TNBC still remains challenging due to the lack of expression of effective molecular targets pertaining to the tumor cell itself. In TNBC standard of care, therapies such as chemotherapy, together with recently introduced immunotherapy with checkpoint inhibitors, often do not result in durable clinical response. Therefore, better understanding of complex interactions between tumor cells, immune cells, and stromal cells mediated by multiple cytokines, chemokines, enzymes, and metabolites in TME is crucial for understanding the mechanisms that underlie tumor cell immune evasion strategies. The aim of this review is to give comprehensive overview of immune cell network and their interactions with cells in TME and possibilities for therapeutic targeting of TME in TNBC. We discuss cancer-associated fibroblasts (CAFs) as an important recently characterized player in TNBC with respect to their role in interactions with immune cells and their impact on tumor invasion. Based on the recently accumulated knowledge, therapies targeting immune suppressive mechanisms and CAF-related tumor-promoting mechanisms in TME hold great potential for clinical evaluation in TNBC.
    Keywords:  cancer associated fibroblasts; triple negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells14171353
  6. Int J Mol Sci. 2025 Sep 04. pii: 8627. [Epub ahead of print]26(17):
    Lysine-Leucine-Rich Frog Skin Antimicrobial Peptides Inhibit Breast Cancer Metastasis by Reprogramming Tumor-Associated Macrophage Polarization.
    Zhenyan Li, Xuan Zhou, Weibing Dong, Ang Li.
      Tumor-associated macrophages (TAMs) are one of the most important components of the tumor microenvironment and play a critical role in promoting tumor invasion and metastasis. These cells have become a new therapeutic target for inhibiting tumor progression. Lysine/leucine-rich antimicrobial peptides have well-documented anticancer activity in vitro, but their immune regulatory activity in human macrophages is not clear. The present study investigated the regulatory effects of lysine/leucine-rich peptides on the polarization of M2-like macrophages and the metastasis of breast cancer cells mediated by M2-like TAMs in the tumor microenvironment (TME). Our results revealed remarkable inhibition of the polarization of M2-like macrophages following treatment with lysine/leucine-rich antimicrobial peptides, which was accompanied by a significant reduction in the expression of the M2-like macrophage-specific factors interleukin-10 (IL-10) and transforming growth factor-β (TGF-β1) and the M2 macrophage-specific marker CD206. The lysine/leucine-rich antimicrobial peptides downregulated the expression of PPARγ and Krüppel-like factor 4 (KLF4) and the phosphorylation of STAT6 in the STAT6 signaling pathway, which resulted in a decrease in IL-10 and TGF-β1. Moreover, we found that lysine/leucine-rich antimicrobial peptide-treated macrophages reduced the migration of cancer cells by inhibiting the phosphorylation of the mTOR, smad2 and ERK proteins during tumor metastasis. These findings highlight the potential of lysine/leucine-rich antimicrobial peptides as therapeutic agents that target M2-like macrophages to inhibit cancer cell metastasis.
    Keywords:  antimicrobial peptide; breast cancer; metastasis; polarization; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/ijms26178627
  7. J Biomed Sci. 2025 Sep 10. 32(1): 87
    TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
    Shukla Sarkar, Chien-I Chang, Jussekia Jean, Meng-Ju Wu.
      Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.
    Keywords:  2-hydroxyglutarate; Epigenetic regulation; Fumarate; Itaconate; Metabolic reprogramming; Oncometabolites; Succinate; TCA cycle; Tumor immunity; α-ketoglutarate
    DOI:  https://doi.org/10.1186/s12929-025-01186-y
  8. Front Biosci (Landmark Ed). 2025 Aug 26. 30(8): 36559
    The Role of Recruited Adipose Stromal Cells and Their Fibroblastic Differentiation in Cancer.
    Lingyi Cai, Mikhail G Kolonin, Dimitris Anastassiou.
      Adipose stromal cells (ASCs) are perivascular mesenchymal progenitors of adipose tissue. In cancer patients, ASCs can mobilize and migrate to the tumor, where they subsequently play an important role in cancer progression. This biological process involves the conversion of recruited ASCs into cancer-associated fibroblasts (CAFs). ASC-derived CAFs influence the tumor microenvironment through extracellular matrix remodeling, vascularization, and immunomodulation. These and other processes mediated by secreted paracrine factors also affect gene expression in carcinoma cells to promote the epithelial-mesenchymal transition (EMT), metabolic adaptation, survival, and invasiveness of cancer cells. ASC-derived CAFs can enhance tumor aggressiveness, accounting in part for the link between obesity and mortality observed in many cancer types that are surrounded by adipose tissue. In this review, we highlight recent findings on the characteristics and functions of ASCs in cancer and discuss their potential as therapeutic targets.
    Keywords:  adipose stromal cells; adipose-derived fibroblasts; cancer-associated fibroblasts; tumor microenvironment
    DOI:  https://doi.org/10.31083/FBL36559
  9. FASEB J. 2025 Sep 15. 39(17): e71023
    UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer.
    Changxin Shao, Shiqi Qiao, Yizi Meng, Tianxiao He, Lifeng Cui, Jin He.
      Tumor-associated macrophages (TAMs) act as a vital player in the immunosuppressive tumor microenvironment (TME) and have received widespread attention in the treatment of cancer in recent times. Nevertheless, simultaneously inducing TAM repolarization and strengthening their phagocytic ability on cancer cells is still a significant challenge. Ferroptosis has received widespread attention due to its lethal effects on tumor cells, but its role in TAMs and its impact on tumor progression have not yet been defined. Here, M2-type tumor-associated macrophages (M2-TAMs) targeted nanobubbles (NBs)-based (M2-pep@SF-NBs) were constructed for ultrasound-controlled delivery of the ferroptosis agonist sorafenib (SF) to enhance macrophage-mediated cancer immunotherapy. SF causes ferroptosis of M2 and regulates repolarization to M1 and promotes intratumoral (cytotoxic T lymphocyte) CTL infiltration, leading to activation of the TME that significantly inhibits tumor growth. Additionally, ultrasound (US)-induced macrophage ferroptosis notably improved the effectiveness of anti-PD-1 (aPD-1) therapy against tumors. M2-pep@SF-NBs were constructed to specifically target macrophage ferroptosis and repolarization, and combining this treatment with aPD-1 exerted significant anti-tumor efficacy. These findings lay the groundwork for deeper exploration of ferroptosis activation in TAMs and the regulation of their infiltration and function, aiming to enhance tumor prevention and therapeutic outcomes.
    Keywords:  ferroptosis; sorafenib; tumor microenvironment; tumor‐associated macrophages; ultrasound‐targeted microbubble destruction
    DOI:  https://doi.org/10.1096/fj.202500974R
  10. Cells. 2025 Sep 07. pii: 1398. [Epub ahead of print]14(17):
    Cancer-Associated Fibroblasts in Solid Tumors and Sarcomas: Heterogeneity, Function, and Therapeutic Implications.
    Omar Badran, Idan Cohen, Gil Bar-Sela.
      Cancer-associated fibroblasts (CAFs) are crucial regulators of the tumor microenvironment (TME), promoting cancer progression, immune suppression, and therapy resistance. Single-cell transcriptomics has identified at least five distinct CAF subtypes: myofibroblastic (myCAFs), inflammatory (iCAFs), antigen-presenting (apCAFs), metabolic (meCAFs), and vascular/developmental (vCAFs/dCAFs), each with unique localization, signaling, and functions. While CAFs are well studied in epithelial cancers, their roles in sarcomas are less understood despite the shared mesenchymal origin of tumor and stromal cells. This overlap blurs the line between malignant and non-malignant fibroblasts, raising fundamental questions about the identity of CAFs in mesenchymal tumors. In this narrative review, we explore the heterogeneity and plasticity of CAFs across solid tumors, focusing on their role in immune evasion, epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy, targeted therapy, and immunotherapy. We highlight emerging evidence on CAF-like cells in sarcomas and their contribution to tumor invasion, immune exclusion, and metastatic niche formation. We also assess new strategies to target or reprogram CAFs and suggest that CAF profiling may serve as a potential biomarker for patient stratification. Understanding CAF biology across various tumor types, including those with dense stroma and immunologically cold sarcomas, is crucial for developing more effective, personalized cancer treatments.
    Keywords:  3D tumor models; CAF-plasticity; cancer-associated fibroblasts; fibroblast heterogeneity; immune modulation; mesenchymal tumors; sarcoma; stromal remodeling; tumor microenvironment; tumor-stroma interaction
    DOI:  https://doi.org/10.3390/cells14171398
  11. Front Immunol. 2025 ;16 1658795
    Progress in targeting tumor-associated macrophages in cancer immunotherapy.
    Wanqiu Xia, Xianghan Zhang, Yaru Wang, Zihan Huang, Xinyu Guo, Lei Fang.
      Tumor-associated macrophages (TAMs) are central to tumor progression, immune suppression, and resistance to therapy, making them promising targets in cancer immunotherapy. TAMs exhibit functional heterogeneity, polarizing into pro-tumor (M2-like) and anti-tumor (M1-like) phenotypes under different microenvironmental cues. M2-like TAMs promote immune evasion, angiogenesis, and metastasis, while M1-like TAMs enhance antitumor immunity. Combining TAM-targeted therapies with immune checkpoint inhibitors is also emerging as a potential strategy to enhance immunotherapy efficacy. This review outlines TAM-mediated immunosuppression mechanisms, including the secretion of VEGF, TGF-β, and immune checkpoint molecules like PD-L1. We also summarize the current strategies targeting TAMs, such as blocking the CD47/SIRPα axis, using CD40 agonists, and PI3Kγ inhibitors, which have shown promise in preclinical studies. Overall, this review underscores TAMs as pivotal therapeutic targets and proposes future directions to optimize combinatorial immunotherapy for enhanced clinical outcomes.
    Keywords:  Tumor-associated macrophages; immune checkpoints; immunosuppression; immunotherapy; treatment resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1658795
  12. Oncol Res. 2025 ;33(9): 2221-2242
    Targeting TAMs & CAFs in melanoma: New approaches to tumor microenvironment therapy.
    Yuriy Mayasin, Maria Osinnikova, Daria Osadchaya, Victoria Dmitrienko, Anna Gorodilova, Chulpan Kharisova, Kristina Kitaeva, Ivan Filin, Valeria Solovyeva, Albert Rizvanov.
      Melanoma is a malignant neoplasm with a high propensity to metastasize, arising from melanocytes and contributing significantly to global morbidity and mortality. Despite the demonstrated efficacy of many immunotherapy approaches, these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells, the extracellular matrix, and blood vessels that form the tumor microenvironment (TME). The TME is known to be heterogeneous and dynamic, exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis. TME has been shown in several studies to promote malignancy, angiogenesis, and metastasis in tumors in general and melanoma in particular. Consequently, a significant number of studies in the field of melanoma therapy have been redirected to investigate the effects of individual TME constituents, their prognostic significance for patients, and the potential of therapeutic intervention to improve overall patient survival. This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment: tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.
    Keywords:  Cancer-associated fibroblast (CAF); Clinical trials; Colony-stimulating factor 1 receptor (CSF1R); Fibroblast activation protein alpha (FAPα); Melanoma; Tumor microenvironment; Tumor-associated macrophage (TAM)
    DOI:  https://doi.org/10.32604/or.2025.064677
  13. Front Oncol. 2025 ;15 1650219
    Ferroptosis in the tumor microenvironment: mechanisms, advances, and therapeutic perspectives.
    Weijuan Gao, Jiani Tan, Chengtao Yu.
      Ferroptosis is a regulated, non-apoptotic form of cell death marked by the accumulation of iron-dependent lipid peroxides. This process causes rapid rupture of the plasma membrane and the release of intracellular contents. Ferroptosis acts as an intrinsic tumor-suppressive mechanism. It plays a crucial role in tumor progression, metastasis, and resistance to standard therapies, including chemotherapy and radiotherapy. Its unique molecular mechanisms confer significant therapeutic potential. In recent years, multiple experimental therapies aiming to induce ferroptosis have been developed for cancer treatment. Although these therapies show promise in controlling tumor growth, their effects on the tumor microenvironment (TME) require further investigation. Recent studies indicate that distinct cell populations within the TME have different sensitivities to ferroptosis. This variability may lead to unintended effects, such as damage to normal cells or increased inflammation, resulting in toxicity. Cells in the TME can either undergo ferroptosis or modulate its regulation through intercellular signaling and interactions. Notably, ferroptosis-related interactions between tumor cells and other components of the TME, such as immune cells, stromal cells, and endothelial cells, are central to TME remodeling. This mini-review summarizes recent advances in ferroptosis mechanisms and highlights the dynamic interplay between ferroptosis and the TME. It also discusses the prospects and challenges of ferroptosis-based cancer therapies.
    Keywords:  antioxidants; ferroptosis; iron; lipid peroxides; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1650219
  14. Trends Cancer. 2025 Sep 10. pii: S2405-8033(25)00203-1. [Epub ahead of print]
    Host and microbiome lipid metabolism in colorectal cancer development and therapy.
    Gabriel Medina Evora, Madita Brauer, Elisabeth Letellier.
      Colorectal cancer (CRC) remains one of the most prevalent cancers, with treatment largely dependent on surgery and chemotherapy, underscoring the need for novel or adjunct therapies. Cancer cells reprogram their lipid metabolism to support proliferation, invasiveness, and chemoresistance, making it a promising therapeutic target. Although several inhibitors of lipogenesis, lipases, lipid uptake, and lipid storage are under investigation in CRC, none have yet shown sufficient efficacy. Importantly, the tumor microenvironment (TME) and the microbiome influence CRC lipid metabolism by supplying compensatory lipids and engaging in crosstalk that affects the efficacy of lipid-targeting therapies. This review describes the role of lipids in CRC and explores how the TME and the gut/tumor microbiome may contribute to current challenges in the development of effective lipid-targeting therapies.
    Keywords:  colorectal cancer; diet; inhibitors; lipid metabolism; microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.005
  15. Adv Sci (Weinh). 2025 Sep 12. e10004
    Integrating Metabolic Modulation and Nanomedicine for Cancer Immunotherapy.
    Xiaosu Zhou, Ruibing Deng, Zunde Liao, Xiaoyu Huang, Junting Huang, Hanlou Yang, Kam W Leong, Yiling Zhong.
      Cancer cells undergo significant metabolic reprogramming to support rapid growth, survival under stress, and resistance to therapies. As our understanding of tumor metabolism and the tumor microenvironment (TME) deepens, there is growing interest in exploiting metabolic vulnerabilities as therapeutic strategies. This review explores key alterations in metabolic pathways, including glucose, amino acid, lipid, nucleotide metabolism, and mitochondrial function, and highlights their impact on tumor progression, the TME, and immune cell function. In addition, the review discusses emerging strategies aimed at targeting these metabolic pathways with a focus on nanomaterial-based therapies. This includes the use of nanoparticles and drug delivery systems designed to modulate immunometabolism within cancer. These innovative approaches aim to reprogram the TME, enhance immune responses, and improve the targeted delivery of therapeutic agents to tumor sites, offering new ways to overcome conventional therapeutic resistance. Finally, the review also addresses the foreseeable challenges and potential future developments in this field, outlining the opportunities and obstacles that must be addressed for the clinical translation of these strategies in cancer therapy.
    Keywords:  immunometabolism; immunotherapy; metabolic reprogramming; nanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202510004
  16. Cancer Med. 2025 Sep;14(17): e71223
    Cellular Senescence and Immunosenescence in Melanoma: Insights From the Tumor Microenvironment.
    Lihua Xiong, Jian Cheng.
       BACKGROUND: Melanoma is one of the most immunogenic malignancies, yet resistance to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable therapeutic success. Emerging evidence indicates that aging-related processes, including cellular senescence and immunosenescence, can reshape the tumor microenvironment (TME) to favor immune evasion and disease progression. Senescent melanoma and stromal cells secrete a senescence-associated secretory phenotype (SASP) that alters immune cell recruitment and function, while immunosenescence leads to diminished cytotoxic responses and the accumulation of dysfunctional or suppressive immune subsets.
    AIM: This review explores the interplay between cellular senescence and immunosenescence in melanoma, highlighting their contributions to tumor progression and immunotherapy resistance, and discusses potential strategies to therapeutically target senescence-related pathways.
    METHODS: A systematic review of studies published between 2000 and 2024 was performed using PubMed, Web of Science, and Scopus. Literature included mechanistic investigations of senescence in melanoma, analyses of immunosenescence in cancer patients, and preclinical or translational studies targeting senescence-related pathways.
    RESULTS AND CONCLUSIONS: Senescent tumor and stromal cells drive a pro-inflammatory and immunosuppressive TME through SASP, while aging immune cells exhibit impaired antigen presentation, reduced cytotoxicity, and increased suppressive subsets. These dual processes form a self-reinforcing cycle of chronic inflammation and immune dysfunction, ultimately undermining the efficacy of ICIs. Targeting senescence, through senolytics, senostatics, or SASP modulators, has shown promise in preclinical models and may restore immune competence in melanoma. However, clinical translation requires further investigation to validate safety and efficacy. Addressing both cellular and immune senescence represents a novel and promising direction to overcome therapeutic resistance and improve melanoma outcomes.
    Keywords:  cellular senescence; immunosenescence; melanoma; senescence‐associated secretory phenotype; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.71223
  17. Front Oncol. 2025 ;15 1630464
    Immunotherapy resistance in triple-negative breast cancer: Molecular mechanisms, tumor microenvironment, and therapeutic implications.
    Zijian Zhou, Qin Zhou.
      Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by high invasiveness, high metastasis rates, and poor prognosis, making it an important focus within global malignancies. Due to the absence of estrogen receptor, progesterone receptor, and HER2 expression, TNBC presents significant challenges in treatment. Metastatic progression markedly increases treatment complexity, drastically reducing patient survival rates. The metastatic and drug resistance processes of TNBC involve complex, multi-step biological mechanisms regulated through various molecular mechanisms and signaling pathways within and outside tumor cells. In recent years, immunotherapy has brought new hope for TNBC. Compared to other breast cancer subtypes, TNBC demonstrates higher immunogenicity, often accumulating a higher mutational burden that generates more neoantigens, thus typically resulting in a tumor microenvironment (TME) enriched with tumor-infiltrating lymphocytes (TILs). Additionally, PD-L1 expression is significantly higher in TNBC compared to other subtypes, closely correlating with TIL abundance. These characteristics position TNBC as a strong candidate for immune checkpoint inhibitor (ICI) therapy. Clinical trials have demonstrated promising efficacy of ICIs in TNBC, overturning previous beliefs that breast cancer is generally insensitive to immunotherapy. This review summarizes recent advances regarding resistance types, molecular mechanisms, associated genes and pathways, the role of the tumor microenvironment, and clinical strategies related to immunotherapy resistance in the neoadjuvant setting of TNBC, aiming to provide insights and guidance for future research exploration and clinical practice.
    Keywords:  drug resistance mechanism; genetic mutations; personalized therapy; review literature; signaling pathways; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1630464
  18. Cancers (Basel). 2025 Sep 05. pii: 2917. [Epub ahead of print]17(17):
    Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors.
    Tereza Andreou, Constantina Neophytou, Fotios Mpekris, Triantafyllos Stylianopoulos.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types-γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells-are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors.
    Keywords:  CAR NK cells; CAR dendritic cells; CAR macrophages; cancer; cell therapy; chimeric antigen receptor (CAR); immunotherapy
    DOI:  https://doi.org/10.3390/cancers17172917
  19. Front Cell Dev Biol. 2025 ;13 1565993
    Lactate modulates the function of myeloid-derived suppressor cells via Ten-Eleven-Translocation-2-mediated demethylation of glucocorticoid-inducible kinase 1 in lung cancer model.
    Ying Chu, Hua Shen, Qiu Li, Bo Shen, Yan Zhang, Deqiang Wang, Wei Zhu, Shengjun Wang, Jie Ma.
       Background: Lactate has been shown to play an important immunosuppressive role in the tumor microenvironment (TME) and promote tumor progression through a variety of different mechanisms of action. Myeloid-derived suppressor cells (MDSCs) are important cells that play an immunosuppressive role in the TME. However, the underlying mechanism by which lactate regulates MDSCs remains unclear. This study aims to explore the molecular mechanism by which lactate regulates the immunosuppressive function of MDSCs in the TME, providing new ideas and targets for anti-tumor immunotherapy targeting MDSCs.
    Methods: This study used the Lewis lung carcinoma cell line to establish a subcutaneous lung cancer model; MDSCs were isolated from the spleens of these mice for subsequent experiments. Protein expression was analyzed by Western blot, mRNA expression by qRT-PCR, protein-DNA interactions by ChIP-qPCR, and DNA methylation by MSP-qPCR and BSP. Exploring the regulatory mechanism of CD38 on the immunosuppressive function of MDSCs by knockdown and overexpression techniques.
    Results: We found that compared with spleen-derived MDSCs (SP-MDSCs) of subcutaneous lung cancer model, tumor-derived MDSCs (T-MDSCs) had stronger immunosuppressive function. Lactate could promote the immunosuppressive function of MDSCs, significantly upregulate the expression of serum and glucocorticoid-inducible kinase 1 (SGK1) in MDSCs. Further studies demonstrated that lactate could downregulate the DNA methylation level of SGK1 by regulating the Ten-Eleven-Translocation-2 (TET2) and TET2 was closely related to the immunosuppressive function of MDSCs and the progression of tumors.
    Conclusion: Lactate can upregulate the expression of SGK1 through demethylation mediated by TET2, enhancing the immunosuppressive function of MDSCs to promote tumor progression. It provides the effective therapeutic targets for anti-tumor therapy.
    Keywords:  DNA methylation; MDSCs; SGK1; TET2; lactate
    DOI:  https://doi.org/10.3389/fcell.2025.1565993
  20. Cancer Pathog Ther. 2025 Sep;3(5): 383-391
    Targeting collagen in "armored and cold" tumors: Overcoming barriers to cancer therapy.
    Shaofei Wang, Jingjing Li, Yulei Zhao.
      Collagen contributes to extracellular matrix formation and stiffness, providing a three-dimensional framework that supports the development and growth of solid tumors. By interacting with specific tumor cell receptors, collagen influences tumor cell signaling pathways, promoting cancer progression and drug resistance. Recent advancements in understanding the tumor extracellular matrix have underscored collagen's role in fostering an immunosuppressive tumor microenvironment (TME) and acting as a barrier to immunotherapy. Understanding the immunosuppressive mechanisms of collagen in the TME has revealed novel therapeutic targets and opportunities. This review highlights the immunoregulatory functions of collagen in the TME and provides a comprehensive overview of integrating collagen scores with traditional immunoscore-based immunotyping methods to enhance response prediction. Additionally, we discuss recent therapeutic developments in collagen targeting and their clinical potential for enhancing anti-cancer immunity.
    Keywords:  Collagen; Extracellular matrix; Immune checkpoint inhibitors; Immunotherapy; Therapeutics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cpt.2024.11.001
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