bims-flamet 2025-08-24 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–08–24
eleven papers selected by
Peio Azcoaga, Biodonostia HRI

Targeting myeloid cells to improve cancer immune therapy.
SensRORing cholesterol to drive protumoral myelopoiesis.
The dual role of Piezo1 in tumor cells and immune cells: a new target for cancer therapy.
Targeting LAIR1-mediated immunosuppression adds a new weapon to our immunotherapy arsenal.
Targeting cholesterol metabolism in tumor and its immune microenvironment: opportunities and challenges.
M1 macrophages - unexpected contribution to tumor progression.
Editorial: Community series in biomarkers in the era of cancer immunotherapy: zooming in from periphery to tumor microenvironment, volume II.
Systemic mRNA aggregates elicit immunologic reprogramming that unlocks anti-cancer immunity.
Mast Cells Drive Ferroptosis in Gastric Tumors as Key Players in the Tumor Immune Microenvironment.
eIF4E Enriched Extracellular Vesicles Induce Immunosuppressive Macrophages through HMGCR-Mediated Metabolic Rewiring.
Stearoyl-CoA desaturase 1: An important factor in lipid metabolism in colorectal cancer.

Front Immunol. 2025 ;16 1623436

Targeting myeloid cells to improve cancer immune therapy.

Hui Chen, Zihan Xu, Judith Varner.

  Tumor immunosuppression remains a major barrier to effective cancer immunotherapy and is often driven by the immunoregulatory activities of innate immune cells, such as myeloid cells within the tumor microenvironment (TME). Myeloid populations-including tumor-associated macrophages (TAMs), dendritic cells, granulocytes, monocytes and myeloid-derived suppressor cells (MDSCs)-play pivotal roles in dampening anti-tumor immune responses and promoting tumor progression. Recent advances in our understanding of myeloid cell biology have unveiled new therapeutic opportunities to disrupt these immunosuppressive mechanisms associated with tumor inflammation. This review highlights key signaling pathways and surface molecules involved in myeloid-mediated immune suppression, including CSF1R, PI3Kγ, mTOR, Syk, MerTK/Axl, and immune checkpoints such as Trem2, LILRBs, VISTA, and CD40. We examine preclinical and clinical findings that support targeting these pathways to reprogram the TME and enhance anti-tumor immunity. By integrating insights from mechanistic studies and therapeutic development, this review underscores the potential of myeloid cell-targeting strategies as promising adjuncts to current cancer immunotherapies. Finally, we discuss future directions and challenges in translating these approaches into durable clinical benefit.

Keywords:  Axl; CSF1R (colony stimulating factor 1 receptor); LILRB; PI3Kgamma; TREM2; immunesuppression; myeloid cell; tumor associated macrophage (TAM)

DOI:  https://doi.org/10.3389/fimmu.2025.1623436
Mol Oncol. 2025 Aug 20.

SensRORing cholesterol to drive protumoral myelopoiesis.

Sara Gennari, Luigi Nezi, Teresa Manzo.

  Protumoral myelopoiesis is a determinant of immunoevasion and tumor spread in many malignancies. In a recent issue of Cancer Discovery, Bleve and colleagues point to cholesterol-driven RORγ activation as the molecular trigger of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) expansion, resulting in defective antitumor response and disease progression.

Keywords:  Protumoral myelopoiesis; RORγ; anti‐tumor response; lipid metabolism

DOI:  https://doi.org/10.1002/1878-0261.70113
Front Immunol. 2025 ;16 1635388

The dual role of Piezo1 in tumor cells and immune cells: a new target for cancer therapy.

Peng Qu, Hongyan Zhang.

  Piezo1, a mechanosensitive ion channel, plays a pivotal and multifaceted role in tumor progression, immune evasion, and therapeutic resistance by transducing extracellular mechanical stimuli-such as matrix stiffness and fluid shear stress-into intracellular calcium influx. In tumor cells, Piezo1 promotes proliferation, invasion, and metastasis by activating oncogenic signaling and contributes to an immunosuppressive TME through regulation of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling. In the immune compartment, Piezo1 integrates mechanical cues with metabolic and epigenetic reprogramming to orchestrate the functions of T cells, macrophages, and natural killer (NK) cells. Notably, Piezo1 deficiency impairs TH9 cell differentiation, diminishes T cell cytotoxicity, and enhances the activity of regulatory T cells (Tregs). Furthermore, Piezo1 expression correlates with distinct tumor immune phenotypes, such as "cold tumors," and with responses to immunotherapy, making it a promising predictive biomarker for treatment efficacy. Given its dual regulatory roles in tumor biology and immune modulation, targeting Piezo1-such as through combination with programmed death-1 (PD-1) blockade-offers a potential strategy to reverse immunosuppression and enhance antitumor immunity. This review summarizes emerging insights into Piezo1's role in cancer progression and immune regulation and highlights its translational potential as a novel target in cancer immunotherapy.

Keywords:  Piezo1; cancer immunotherapy; immune modulation; mechanosensitive ion channel; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1635388
J Clin Invest. 2025 Aug 15. pii: e194924. [Epub ahead of print]135(16):

Targeting LAIR1-mediated immunosuppression adds a new weapon to our immunotherapy arsenal.

Ezri P Perrin, Hannah K Dorando, Jacqueline E Payton.

Leukocyte-associated Ig-like receptor 1 (LAIR1) is a collagen-binding inhibitory immune receptor that negatively regulates cellular activation. In this issue of the JCI, Tao et al. show that LAIR1-inhibitory signaling plays an important role in immunosuppressive M2-like tumor-associated macrophages (TAMs) in aggressive brain tumors. LAIR1 KO, antibody blockade, and an immunotherapy that incorporates a LAIR1-inhibitory module into a chimeric antigen receptor (CAR) all led to increased antitumor activity by CAR T cells, reduced M2-like TAMs, altered collagen networks, and increased survival rates in mouse tumor models. These findings demonstrate an innovative immunotherapeutic approach for cancer that leverages LAIR1 inhibition to combat multiple tumor immune evasion strategies.

DOI: https://doi.org/10.1172/JCI194924
Biochim Biophys Acta Rev Cancer. 2025 Aug 14. pii: S0304-419X(25)00164-7. [Epub ahead of print]1880(5): 189422

Targeting cholesterol metabolism in tumor and its immune microenvironment: opportunities and challenges.

Ziyi Wang, Xinyan Li, Xiangyu Sun.

  Cholesterol metabolism provides cell and organelle membrane components, and its precursors and derivatives exert a variety of biological functions. Dysregulated cholesterol metabolism has emerged as a hallmark of tumors. In the tumor microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism to drive tumorigenesis and tumor development. Clinical studies and mechanistic investigations into cholesterol metabolism pathways have uncovered novel metabolic vulnerabilities that hold promise for cholesterol metabolism-targeted therapies for cancer. Moreover, recent studies highlight that manipulating cholesterol metabolism could reshape the immunological landscape and re-boost anti-tumor immunity. Thus, it is critical to deeply discuss the role of cholesterol metabolism in tumors and immune microenvironment to extend this knowledge into current immunotherapies. In this review, we summarize current insights into reprogrammed cholesterol metabolism in tumors and explore the complex interplay between cholesterol metabolism and anti-tumor immunity in diverse immune components within the tumor microenvironment. These findings may provide novel clinical strategies for targeting cholesterol metabolism in the context of cancers.

Keywords:  Cholesterol; Immunity; Immunotherapy; Metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189422
Front Immunol. 2025 ;16 1638102

M1 macrophages - unexpected contribution to tumor progression.

Olga V Kovaleva, Madina A Rashidova, Vasiliy V Sinyov, Olga S Malashenko, Alexei Gratchev.

  The anti-tumor role of the immune system has long been associated with interferon-γ-mediated activation of immune cells and their ability to recognize and eliminate transformed cells. Fundamental principles of tumor immunoediting describe a dynamic interplay between the immune system and neoplastic cells, wherein immune pressure can paradoxically shape tumor evolution. Within this context, macrophages, natural killer cells, and T lymphocytes are central effectors of anti-tumor immunity. Traditionally, macrophages exhibiting M1 phenotype are characterized by high cytotoxic potential and considered important contributors to tumor eradication. In contrast, M2-polarized tumor-associated macrophages are associated with immune suppression and tumor progression. However, recent evidence challenges this binary paradigm. It is increasingly evident that M1 macrophages, while initially exerting anti-tumor effects, can also promote tumor progression by applying sustained cytotoxic pressure that selects for more malignant and immune-resistant tumor clones. This phenomenon represents an unexpected and overlooked contribution of cytotoxic macrophages to tumor progression. In this review, we examine the complex, context-dependent function of M1 macrophages and reassess current strategies aimed at enhancing their cytotoxicity. While such approaches may offer short-term benefits, they risk driving clonal selection of aggressive, immune-evasive tumor cells. Therefore, we propose a paradigm shift: instead of promoting M1 polarization alone, therapeutic strategies should consider the broader consequences of macrophage-tumor interactions. A nuanced understanding of macrophage plasticity and tumor dynamics is essential for designing effective immunotherapies. Recognizing the paradoxical role of M1 macrophages is critical to avoiding unintended support of tumor evolution and improving treatment outcomes.

Keywords:  ADCC; ADCP; immunotherapy; inflammation; innate immunity; macrophage; tumor

DOI:  https://doi.org/10.3389/fimmu.2025.1638102
Front Immunol. 2025 ;16 1662278

Editorial: Community series in biomarkers in the era of cancer immunotherapy: zooming in from periphery to tumor microenvironment, volume II.

Jehad Charo, Cristina Maccalli.



Keywords:  biomarkers; cancer; fibroblasts; immunotherapy; statistic and modeling; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1662278
Hum Vaccin Immunother. 2025 Dec;21(1): 2543599

Systemic mRNA aggregates elicit immunologic reprogramming that unlocks anti-cancer immunity.

Hector R Mendez-Gomez, John A Ligon, Ashley P Ghiaseddin, Elias J Sayour.

  Successful cancer immunotherapy requires novel approaches that overcome intratumoral immunosuppression and peripheral tolerance. In a recent manuscript describing intravenously administered mRNA-loaded lipid particle aggregates (RNA-LPAs), we demonstrate the ability to reprogram both the tumor microenvironment and periphery enabling cancer-specific immunity simultaneously generated to compete against immunologically 'cold' malignancies like glioblastoma.

Keywords:  cancer; immunotherapy; mRNA vaccines

DOI:  https://doi.org/10.1080/21645515.2025.2543599
OMICS. 2025 Aug 19.

Mast Cells Drive Ferroptosis in Gastric Tumors as Key Players in the Tumor Immune Microenvironment.

Fatma Sert, Ozlem Ulucan.

  Ferroptosis, an iron-dependent form of oxidative cell death, plays a critical role in cancer progression and immune regulation. However, the functional connections of ferroptosis with specific immune cell types remain poorly defined, limiting the future possibilities to harness ferroptosis for cancer biology, diagnosis, and treatment. To address this knowledge gap, we conducted an integrated transcriptomic analysis to investigate ferroptosis-related immune dynamics in gastric cancer (GC). We utilized GC datasets from The Cancer Genome Atlas-stomach adenocarcinoma (n = 412) and the GSE66229 (n = 300) that were clustered into three GC immune subtypes based on single-sample Gene Set Enrichment Analysis scores of 29 immune gene sets. Bulk RNA-seq analysis revealed that the immune-inflamed subtype (HIS) of tumor samples in both GC datasets exhibited the highest ferroptosis enrichment and showed a positive correlation with activated mast cells and neutrophils. Given the regulatory role of mast cells in the tumor microenvironment (TME), particularly in recruiting neutrophils, we further examined their link to ferroptosis. In a fibroblast-mast cell coculture RNA-seq data (GSE223179), fibroblasts exhibited increased ferroptosis enrichment, supporting a mast cell-mediated influence. Single-cell RNA-seq data confirmed stronger interactions between mast cells and fibroblasts in GC compared to normal tissues. Specifically, they revealed a positive correlation between mast cell activity and ferroptosis enrichment in tumor-associated fibroblasts. In conclusion, these findings suggest that mast cells may promote ferroptosis in the TME through paracrine signaling, possibly via annexin and cyclophilin A. By uncovering this novel pathophysiological axis, our study reveals a previously unrecognized role of mast cells in regulating ferroptosis within the TME. The findings call for translational and experimental medical research and have potential implications for innovation toward GC diagnostics and therapeutics.

Keywords:  ferroptosis; gastric cancer; integrative biology; mast cells; scRNA-seq; tumor immune microenvironment

DOI:  https://doi.org/10.1177/15578100251366980
Adv Sci (Weinh). 2025 Aug 18. e06307

eIF4E Enriched Extracellular Vesicles Induce Immunosuppressive Macrophages through HMGCR-Mediated Metabolic Rewiring.

Sonam Mittal, Minal Nenwani, Ishaque Pulikkal Kadamberi, Sudhir Kumar, Olamide Animasahun, Jasmine George, Shirng-Wern Tsaih, Prachi Gupta, Mona Singh, Anjali Geethadevi, Chandrima Dey, Noah Meurs, Ajay Shankaran, Pradeep Chaluvally Raghavan, Deepak Nagrath, Sunila Pradeep.

  Tumor driven immune suppression poses a significant impediment to the success of immunotherapy in ovarian cancer. Among the various mechanisms contributing to immune suppression, intracellular communication facilitated by tumor-derived extracellular vesicles (EVs) within the tumor microenvironment emerges as a pivotal factor influencing tumor growth. Here, it is demonstrated that extracellular vesicle-packaged eIF4E from tumor cells alters protein translation in macrophages, contributing to antitumor immune response. Mechanistically, tumor derived EV-packaged eIF4E significantly enhances the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), driving the synthesis and secretion of cholesterol. This, in turn, activates macrophages and causes immunosuppression through the X-box binding protein 1 and Programmed death-ligand 1 (XBP1/PD-L1) axis. Strikingly, both genetic and pharmacological depletion of HMGCR in macrophages effectively restores their antitumor activity. Clinically, elevated HMGCR expression in tumor-associated macrophages is associated with poor survival outcomes in ovarian cancer patients. The pivotal role of eIF4E is underscored here as a key signaling mediator, facilitating the communication between tumor and immune cells via EVs to promote immune suppression and suggesting HMGCR as a potential therapeutic target for tumor immunotherapy.

Keywords:  PD‐L1; eIF4E; extracellular vesicles; metabolism; ovarian cancer; tumor associated macrophages

DOI:  https://doi.org/10.1002/advs.202506307
Biochem Pharmacol. 2025 Aug 14. pii: S0006-2952(25)00504-0. [Epub ahead of print]242(Pt 1): 117239

Stearoyl-CoA desaturase 1: An important factor in lipid metabolism in colorectal cancer.

Xinzhu Xue, Fang Zhu, Yinnan Chen.

  Colorectal cancer is among the most prevalent cancers globally. It is frequently accompanied by alterations in three metabolic pathways, of which lipid metabolism is particularly important. Recent studies have found that stearoyl-CoA desaturase 1, an important desaturase in lipid metabolism, is crucial in the progression of most tumor cells. This review summarizes the structure and function of stearoyl-CoA desaturase 1, its role in lipid metabolism, its effect on tumor progression, upstream factors regulating stearoyl-CoA desaturase 1 expression, stearoyl-CoA desaturase 1-related reports in colorectal cancer research in the past 5 years, and the potential use of stearoyl-CoA desaturase 1 in future clinical treatment.

Keywords:  Colorectal cancer; Drug resistant; Ferroptosis; Lipid metabolism; Stearoyl-CoA desaturase 1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bcp.2025.117239