bims-flamet 2025-07-20 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–07–20
27 papers selected by
Peio Azcoaga, Biodonostia HRI

The Role of Fibroblasts in Melanoma Development: From Tumor Microenvironment Remodeling to Pre-Metastatic Niche Formation.
Revisiting TAM polarization: beyond M1- and M2-type TAM toward clinical precision in macrophage-targeted therapy.
Hypoxia and immunometabolism in the tumor microenvironment: insights into mechanisms and therapeutic potential.
Mechanism of crosstalk between Helicobacter pylori and immune stromal cells in the development and occurrence of gastric cancer.
Metastasis-promoting functions of myeloid cells.
Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
Tumor-Associated Macrophage in Breast Tumor Microenvironment.
Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor.
p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer.
MicroRNAs in Cancer Immunology: Master Regulators of the Tumor Microenvironment and Immune Evasion, with Therapeutic Potential.
Multidimensional characteristics of the tumor microenviron-ment and advances in therapeutic intervention strategies.
Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.
Bridging the tumor microenvironment: the pivotal role of cancer-associated fibroblasts in tumor cachexia development.
What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.
Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches.
Traditional Chinese medicine in the prevention and treatment of lung cancer metastasis by regulating tumor-associated macrophages: a narrative review.
Neuroimmunology-driven CAR T-cell therapeutics for gliomas: translational challenges and clinical trial paradigm innovation.
The tumor microbiome in cancer progression: mechanisms and therapeutic potential.
Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions.
Relaxin-2-secreting CAR-T cells exhibit enhanced efficacy in stromal-rich xenograft tumors.
Regulation of the tumor microenvironment by Traditional Chinese Medicine: current progress and future perspectives in oncology.
Targeting Siglec-10/α3β1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer.
Optimal therapy schedule of chimeric antigen receptor (CAR) T cell immunotherapy.
Review: radiotherapy-mediated B cells within the TLS influence the tumor microenvironment.
Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands.
Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets.

Int J Mol Sci. 2025 Jun 26. pii: 6132. [Epub ahead of print]26(13):

The Role of Fibroblasts in Melanoma Development: From Tumor Microenvironment Remodeling to Pre-Metastatic Niche Formation.

Immacolata Belviso, Raffaele Pastore, Aldo Mileo, Emiliano Del Genio, Stefania Boccia, Stefano Palermi, Carmine Sellitto, Maria Letizia Motti.

  Melanoma is the most aggressive form of skin cancer, and despite significant therapeutic advances over the past decade, a substantial number of patients still progress to a fatal outcome. The initiation and progression of melanoma are strongly influenced by interactions between melanoma cells and other components of the tumor microenvironment (TME). In this review, we focus on the interplay between fibroblasts resident in the tumor microenvironment and tumor cells. In particular, we examine the molecular mechanisms through which melanoma cells induce the transformation of resident fibroblasts into their active form, known as cancer-associated fibroblasts (CAFs). We also explore the role of CAFs in shaping the melanoma microenvironment (MME) and in organizing the pre-metastatic niche, a specialized microenvironment that forms in distant organs or tissues to support the survival and expansion of metastatic melanoma cells. Finally, we discuss emerging therapeutic strategies aimed at disrupting the interactions between CAFs, melanoma cells, and other components of the tumor microenvironment to improve treatment outcomes.

Keywords:  cancer-associated fibroblasts (CAFs); extra cellular matrix (ECM); fibroblast; melanoma; metastasis; pre-metastatic niche; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/ijms26136132
Exp Mol Pathol. 2025 Jul 14. pii: S0014-4800(25)00032-2. [Epub ahead of print]143 104982

Revisiting TAM polarization: beyond M1- and M2-type TAM toward clinical precision in macrophage-targeted therapy.

Qingqing Wang, Wenxue Ma.

  Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), significantly influencing cancer progression and therapeutic responses. TAMs polarize into M1 or M2 phenotypes, exerting distinct functional roles. M1-type macrophages promote inflammation and tumor cell destruction, whereas M2-type macrophages facilitate immune suppression, angiogenesis, and metastasis. However, inconsistencies and mischaracterizations in the literature regarding TAM classification have led to confusion in the field, potentially impeding the development of effective macrophage-targeted immunotherapies. This commentary highlights the need for clear and standardized nomenclature, clarifies the functional distinctions between M1- and M2- type TAMs, and explores the signaling pathways and environmental factors driving their polarization. We also discuss emerging TAM subtypes and the therapeutic significance of accurate classification, including macrophage reprogramming strategies. Standardizing terminology and addressing misconceptions will be critical to advancing macrophage-based immunotherapies and improving clinical outcomes in cancer treatment.

Keywords:  Cancer immunotherapy; M1 and M2 macrophages; M2 macrophage subtypes; Macrophage polarization; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1016/j.yexmp.2025.104982
Cancer Lett. 2025 Jul 11. pii: S0304-3835(25)00481-1. [Epub ahead of print]631 217913

Hypoxia and immunometabolism in the tumor microenvironment: insights into mechanisms and therapeutic potential.

Cen Wu, Tianhua Xu, Heyang Zhang, Yile Hu, Jinghua Jiao, Kun Qiu, Jia Gu, Wenya Li, Lei Sun.

  The tumor microenvironment (TME), regulated by both intrinsic oncogenic factors and immune metabolic processes, has become an increasing focus of research in recent years. Typical features of the TME include hypoxia, metabolic dysregulation, and immunosuppression. Metabolic reprogramming provides tumors with energy and biosynthetic compounds to meet the nutritional requirements for proliferation. Meanwhile, immune metabolism influences tumor cells to shape the tumor immunosuppressive microenvironment by altering immune cell function and phenotype. Tumor hypoxia signaling specifically fosters the development of immunosuppressive TME by regulating immune metabolism, which, in turn, supports the progression of malignant tumors through modulation of their biological behaviors. This review comprehensively explores the metabolic regulation of hypoxia and immune metabolism during the dynamic evolution of tumor-adapted TME. In the context of the intricate interplay between hypoxia and immunometabolism, the prospects and challenges associated with immunometabolism in the clinical management of tumors are systematically addressed.

Keywords:  Immune evasion; Immunosuppressive microenvironment; Metabolic competition; Tumor hypoxia; Tumor-targeted therapy

DOI:  https://doi.org/10.1016/j.canlet.2025.217913
Discov Oncol. 2025 Jul 12. 16(1): 1318

Mechanism of crosstalk between Helicobacter pylori and immune stromal cells in the development and occurrence of gastric cancer.

Yang Wu, Runbing Zhang, Tian Li, Jiucong Zhang, Xiaohui Yu, Xiaofeng Zheng.

  Helicobacter pylori (Hp) has been classified as a class I carcinogen in gastric cancer, and one of the important mechanisms by which it affects the gastric environment and promotes cancerogenesis is by triggering inflammation.Inflammatory responses caused by Hp's 'crosstalk' with various types of cells in the microenvironment of the gastric tumour play a key role in cancer progression, but the exact mechanism of its 'crosstalk' is still unclear. This paper focuses on the regulatory impact of Hp infection on the tumor microenvironment, systematically explores the activation process of immune stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), and myeloid-derived suppressor cells by directly or indirectly promoting the secretion of inflammatory factors by Hp, and analyzes the molecular mechanism of these cells that influence the occurrence and development of gastric cancer through multiple signal pathways, in order to provide innovative theoretical basis for the development of accurate prevention and treatment strategies for Hp infection-related gastric cancer.

Keywords:  Crosstalk; Gastric cancer; Helicobacter pylori; Immune stromal cells

DOI:  https://doi.org/10.1007/s12672-025-03163-1
Cancer Metastasis Rev. 2025 Jul 15. 44(3): 61

Metastasis-promoting functions of myeloid cells.

Sergei Kusmartsev.

  The tumor metastatic dissemination and colonization is a highly complex, multi-step process that requires cooperation between cancer and host cells. Among these, cells of myeloid lineage mobilized from the bone marrow are crucial in facilitating tumor metastatic outgrowth. Recent studies indicate that myeloid cells of bone marrow origin, including myeloid-derived suppressor cells (MDSCs), macrophages, and progenitor cells, promote distant metastasis through immunological and non-immunological mechanisms. These cells are key contributors to creating an immunosuppressive microenvironment in the invaded tissue and draining lymph nodes, protecting metastatic cells from immunosurveillance, and promoting resistance to immunotherapy. Furthermore, the myeloid cells mediate the remodeling of the extracellular matrix (ECM) in a metastatic niche via enzymes MMP9 and Hyal2, stimulating angiogenesis and establishing a metastasis-permissive microenvironment. This review describes recent findings demonstrating the metastasis-promoting functions of recruited marrow-derived myeloid cells throughout metastatic colonization and suggests new therapeutic avenues.

Keywords:  Hyaluronidase 2 (Hyal2); Immune evasion; Macrophages; Metalloproteinase 9 (MMP9); Myeloid-derived supressore cells (MDSCs); Tumor metastases

DOI:  https://doi.org/10.1007/s10555-025-10278-y
J Exp Med. 2025 Sep 01. pii: e20241426. [Epub ahead of print]222(9):

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.

Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho.

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20241426
Int J Mol Sci. 2025 Jun 21. pii: 5973. [Epub ahead of print]26(13):

Tumor-Associated Macrophage in Breast Tumor Microenvironment.

Lingyao Ma, Yuexinzi Jin, Jian Xu, Jiexin Zhang.

  Breast cancer (BC) is the most common cancer in women worldwide. It is one of the main causes of cancer-related mortality. The breast tumor microenvironment (Br-TME) has emerged as an important factor related to BC development and prognosis. Tumor-associated macrophages (TAMs) are the main effector cells in the Br-TME; they play key roles in regulating angiogenesis, immunosuppression, metastasis, and chemoresistance in BC patients. In this review, we introduce the macrophage niche in the Br-TME, particularly emphasizing the origin of TAMs. Next, we summarize the typical pathways and molecular mechanisms of the interactions between TAMs and various other components in the Br-TME. Finally, we provide an overview of drugs that target TAMs and discuss the prevailing technologies for drug delivery in the context of BC treatment. Identification of the dynamic variations in tumor-promoting TAMs will help reveal the key links that drive BC progression. This review provides a theoretical basis for upcoming clinical trials that may substantially benefit patients.

Keywords:  breast cancer; nanodrug delivery system; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3390/ijms26135973
Cell Immunol. 2025 Jul 14. pii: S0008-8749(25)00087-5. [Epub ahead of print]415-416 105001

Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor.

Kai Yan, Zhongdang Xiao.

  Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1-dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1-mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.

Keywords:  BCMA; CAR-T; CD19; PD1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellimm.2025.105001
bioRxiv. 2025 May 10. pii: 2025.05.08.652949. [Epub ahead of print]

p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer.

Priyanka Rajan, Robert Zollo, Yanqi Guo, Mohammed Alruwaili, Justin Zonneville, Mackenzie Lieberman, Brian Morreale, Caitlin James, Mark Long, Scott H Olejniczak, Joseph Barbi, Scott I Abrams, Andrei V Bakin.

Metastatic breast cancer (MBC) is a life-threatening disease with limited therapeutic options. The immune suppressive tumor microenvironment (TME) limits the potency of the antitumor immune response and facilitates disease progression and metastasis. Our current study demonstrates that p38α is a druggable target in the TME that regulates the outcome of the immune-tumor interaction. The study revealed that systemic blockade of p38α reduces metastasis, and this anti-metastatic response is negated by depletion of CD8 + T cells. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38α by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8 + T cell phenotype. Immunophenotyping analyses demonstrated that p38 blockade reduced the expression of multiple inhibitory receptors on CD8 + T cells (i.e., PD-1, LAG-3, CTLA-4), indicating a reversal of immune exhaustion and enhanced immune activation systemically and in the TME. In contrast, p38 blockade did not exhibit inhibitory effects on T cells in proliferation assays in vitro and did not affect the proportion of regulatory T cells in vivo . The major negative impact of p38 blockade in vivo was on the myeloid populations, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Further, tumor p38α activity was required for the expression of cytokines/chemokines and tumor-derived exosomes with high chemotactic capacity for myeloid cells. Altogether, this study highlights a previously unrecognized p38α-driven pathway that promotes an immune suppressive TME and metastasis, and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.
STATEMENT OF SIGNIFICANCE: This study highlights a previously unrecognized p38α-driven tumor pathway that promotes an immune suppressive microenvironment and metastasis, and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.

DOI: https://doi.org/10.1101/2025.05.08.652949
Cancers (Basel). 2025 Jun 27. pii: 2172. [Epub ahead of print]17(13):

MicroRNAs in Cancer Immunology: Master Regulators of the Tumor Microenvironment and Immune Evasion, with Therapeutic Potential.

Erfan Zare, Seyyed Mohammad Yaghoubi, Maedeh Khoshnazar, Sina Jafari Dargahlou, Janvhi Suresh Machhar, Zihan Zheng, Pascal H G Duijf, Behzad Mansoori.

  MicroRNAs (miRNAs) are pivotal modulators of tumor progression and immune function. Given the central role of the immune system in recognizing and eliminating malignant cells, understanding how miRNAs influence immune responses has become essential for advancing cancer therapy. This review explores the emerging roles of miRNAs in orchestrating cancer immunology, emphasizing their regulation of tumor immune surveillance, immune equilibrium, immune evasion, and immunometabolism. We further illustrate how specific miRNAs modulate the tumor microenvironment by shaping immune cell phenotypes, cytokine networks, and antigen presentation. Some miRNAs enhance cytotoxic T lymphocyte activity, while others promote immune escape by expanding regulatory T cells and myeloid-derived suppressor cells. miRNAs also regulate immune checkpoints (e.g., PD-L1 and CTLA-4), metabolic reprogramming, and stress responses that collectively influence tumor immunogenicity. Additionally, miRNAs are gaining traction as biomarkers for immune activity and predictors of immunotherapy response. Therapeutically, miRNA mimics and inhibitors can enhance anti-tumor immunity, particularly when combined with advanced delivery platforms or immune checkpoint inhibitors. However, challenges such as delivery specificity, off-target effects, and the context-dependent nature of miRNA activity remain significant barriers to clinical translation. Despite shortcomings, miRNAs represent a class of immune regulators with substantial therapeutic potential. Accelerated progress in miRNA-guided therapies is anticipated through deepening insights into miRNA regulatory networks, coupled with integrative multi-omics and AI-driven analytical frameworks. Altogether, miRNAs are a promising frontier in next-generation cancer immunotherapy and precision oncology.

Keywords:  cancer; equilibrium; evasion; immunology; immunometabolism; miRNA; surveillance; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17132172
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2025 Jul 16. 1-11

Multidimensional characteristics of the tumor microenviron-ment and advances in therapeutic intervention strategies.

Hongdan Chen, Long Zhang, Chong Li.

  The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied "classical" TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding of the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotem-poral heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and explores their integration with precision drug delivery strategies. We highlight recent progress in therapeutic interventions targeting the classical TME, mechanical forces, and microbiota-related pathways, and propose interdisciplinary approaches aimed at facilitating the development of more personalized and effective anticancer therapies.

Keywords:  Mechanical microenvironment; Microbial microenvironment; Pharmacological intervention strategy; Review; Tumor microenvironment

DOI:  https://doi.org/10.3724/zdxbyxb-2025-0090
Curr Opin Cell Biol. 2025 Jul 14. pii: S0955-0674(25)00105-X. [Epub ahead of print]96 102567

Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.

Fernanda G Kugeratski, Emily J Kay, Sara Zanivan.

Cancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest in the field of anticancer therapy: immunotherapy, metabolism, and extracellular vesicles. We also highlight the substantial role of CAFs in modulating the immune microenvironment and the recent advances in targeting CAFs for cancer treatment.

DOI: https://doi.org/10.1016/j.ceb.2025.102567
Mol Cancer. 2025 Jul 14. 24(1): 194

Bridging the tumor microenvironment: the pivotal role of cancer-associated fibroblasts in tumor cachexia development.

Guoming Chen, Bonan Chen, Yilin Wu, Hao Nie, Zilan Zhong, Shuyang Yang, Rui Qin, Wei Kang, Cheng Zhang, Ning Wang, Yibin Feng.



Keywords:  Cachexia; Cancer-associated fibroblasts (CAFs); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12943-025-02379-7
J Clin Invest. 2025 Jul 15. pii: e191940. [Epub ahead of print]135(14):

What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.

Colin Sheehan, Alexander Muir.

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.

DOI: https://doi.org/10.1172/JCI191940
Acta Pharm Sin B. 2025 Jun;15(6): 2930-2944

Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches.

Ahmed Rakib, Md Abdullah Al Mamun, Mousumi Mandal, Priti Sinha, Udai P Singh.

  Now recognized as a global health crisis, obesity has been linked to an increased risk of many types of cancer, including those of the breast, colon, rectum, uterus, gallbladder, and ovary. Obesity and cancer share several characteristics at the cellular, molecular, and epigenetic levels. Obesity is characterized by chronic inflammation of the adipose tissue (AT), resulting in genotoxic stress that further induces metabolic complications and contributes to the initiation and progression of cancer. The excessive accumulation of AT provides adipokines and lipids to engage tumor cells with stromal and immune cells to infiltrate carcinomas and secrete a plethora of cytokines, chemokines, and growth factors within the tumor microenvironment (TME) that contribute to carcinogenesis. Obesity also alters the metabolic reprogramming of immune cells, including macrophages, neutrophils, and T cells, thereby providing a suitable environment for the growth and progression of cancer. Obesity-associated metabolic dysregulation also perturbs the gut microbiome, which produces metabolites that can further increase the risk of cancer progression. This review will discuss links between obesity and cancer progression, including several crucial pathways that bridge the crosstalk between obesity-associated changes in AT inflammation, immune cells, adipokines, chemokines, and tumor cells to support cancer progression. We will also discuss our insights into the mechanisms by which obesity-driven factors influence metabolic reprogramming and touch base on how obesity mediates microbiome dysbiosis to alter metabolite and affect cancer progression. Altogether, this review highlights the crossroads of the obesity-cancer axis, describes its salient features, and presents possible therapeutic approaches for obesity-related cancers.

Keywords:  Adipokines; Adipose tissue; Cancer; Glucagon-like peptide-1; Metabolic reprogramming; Metabolism; Microbiome; Obesity

DOI:  https://doi.org/10.1016/j.apsb.2025.04.029
Transl Lung Cancer Res. 2025 Jun 30. 14(6): 2281-2295

Traditional Chinese medicine in the prevention and treatment of lung cancer metastasis by regulating tumor-associated macrophages: a narrative review.

Xinyi Tu, Baozhen An, Haolong Qi, Na Zhang, Yanqiu Liu.

   Background and Objective: Lung cancer remains the leading cause of cancer-related mortality globally, with metastasis representing the principal determinant of poor clinical outcomes. Tumor-associated macrophages (TAMs), as key components of the tumor microenvironment (TME), play pivotal roles in modulating immune responses, tumor progression, and metastatic dissemination. Traditional Chinese medicine (TCM) has demonstrated potential in regulating TAM polarization, thereby inhibiting tumor metastasis. This review aims to comprehensively summarize the current evidence on how TCM modulates TAMs to prevent and treat lung cancer metastasis.
Methods: We conducted a systematic search of literature on TAMs, lung cancer metastasis, and TCM published between 2016 and 2025. Following initial screening of retrieved articles, relevant sources were cross-referenced to identify additional studies.
Key Content and Findings: This review presents a comprehensive summary of recent advances in the modulation of TAMs by TCM in the setting of lung cancer metastasis. TCM-derived compounds and classical herbal prescriptions have demonstrated the ability to reprogram TAMs from an immunosuppressive M2-like phenotype to an immunostimulatory M1-like phenotype. Mechanistically, these agents exert their effects by modulating multiple signaling pathways, including TLR4/NF-κB, STAT3/STAT6, PI3K/AKT, and STING/TBK1/IRF3 pathways, as well as key cytokine networks involving interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Representative monomers, including curcumin, calycosin, and polyphyllin VII, as well as classical formulas such as Bu-Fei decoction (BFD) and Kejinyan decoction, exhibit anti-metastatic activity by reprogramming the immunosuppressive TME and enhancing anti-tumor immune responses.
Conclusions: TCM represents a promising strategy for suppressing lung cancer metastasis by targeting TAMs and restoring immune homeostasis. Future research should focus on the standardization of TCM formulations, mechanistic elucidation, and translational validation in clinical settings. Integrating TCM with contemporary immunotherapies may yield synergistic benefits and advance precision oncology for metastatic lung cancer.

Keywords:  Tumor-associated macrophages (TAMs); lung cancer metastasis; polarization; traditional Chinese medicine (TCM)

DOI:  https://doi.org/10.21037/tlcr-2025-380
Cancer Lett. 2025 Jul 15. pii: S0304-3835(25)00497-5. [Epub ahead of print]631 217928

Neuroimmunology-driven CAR T-cell therapeutics for gliomas: translational challenges and clinical trial paradigm innovation.

Zhipeng Li, Fan Yang, Siyuan Lu, Xinhao Wu, Shenglong Li, Minghao Wang.

  Glioma, a category of the most lethal primary brain tumors, remains incurable despite multimodal therapy combining maximal resection, radiation, and temozolomide. These interventions invariably fail due to residual invasive cells, molecular heterogeneity, and an immunosuppressive tumor microenvironment (TME) reinforced by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The blood-brain barrier (BBB) further limits therapeutic access, while antigen escape and T-cell exclusion mechanisms drive relapse. Chimeric antigen receptor (CAR) T-cell therapy, transformative in relapsed B-cell malignancies with sustained remission rates, faces formidable yet surmountable barriers in solid tumors. Recent advances in CAR-T trials targeting glioma-associated antigens demonstrate partial intracranial activity, albeit with transient efficacy, underscoring the need for neuroimmunology-informed engineering. This review critically evaluates CAR-T strategies countering glioma-specific resistance: bispecific antigen targeting combats tumor plasticity, cytokine-armored designs neutralize immunosuppression, and innovative delivery routes enhance CNS bioavailability. Early clinical outcomes reveal critical divergence points from hematologic success, including antigen loss due to glioma's evolutionary capacity and T-cell exhaustion within hypoxic niches. Emerging solutions integrate CRISPR-edited allogeneic platforms with combinatorial immunomodulation (e.g., myeloid-targeting) and delivery innovations to address these barriers. We further dissect translational priorities including neurotoxicity mitigation and scalable manufacturing for infiltrative glioma phenotypes. By converging advances in immune-engineering, TME remodeling, and biomarker-driven trial designs, this work proposes a roadmap to achieve durable CAR-T efficacy in GBM. The synthesis bridges mechanistic insights into glioma-immune interactions with clinical translation strategies, aiming to transcend current limitations of transient cytoreduction and establish CAR-T therapy as a cornerstone of neuro-oncologic practice.

Keywords:  Chimeric antigen receptor T-cell therapy; Clinical trial design; Glioblastoma; Neuroimmunology; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217928
Mol Cancer. 2025 Jul 15. 24(1): 195

The tumor microbiome in cancer progression: mechanisms and therapeutic potential.

Wanting Zhang, Yuhang Xiang, He Ren, Yilin Liu, Qi Wang, Mengdi Ran, Wanting Zhou, Lu Tian, Xianhui Zheng, Cong Qiao, Yifei Liu, Meisi Yan.

  The tumor microbiome (TM) comprises diverse microbial communities, such as bacteria, fungi, and viruses. Recent advancements in microbial sequencing technologies have improved our understanding of the distribution and functional roles of microbes in solid tumors. The TM is formed through several mechanisms, such as direct invasion of mucosal barriers, diffusion from adjacent normal tissues, metastasis of tumor cells, and dissemination via blood and lymphatic circulation. Microbes play a critical role in the tumor microenvironment (TME), and the TM has a heterogeneous composition in different types of cancer. This heterogeneity affects tumor development, progression, and response to treatment. The TM modulates tumor cell physiology and immune responses via several signaling pathways, such as WNT/β-catenin, NF-κB, toll-like receptors (TLRs), ERK, and stimulator of interferon genes (STING). Extensive studies have characterized the role of TM in tumor progression, revealing the importance of genetic abnormalities, epigenetic changes, metabolic regulation, invasion and metastasis, and chronic inflammatory responses. The role of TM in cancer treatment, especially in immunotherapy, has received increasing attention, demonstrating significant regulatory potential. This review provides an in-depth overview of the development of TM detection technologies, explores its potential origins and heterogeneity, and elucidates the mechanisms by which TM contributes to tumorigenesis or tumor suppression. Furthermore, this review explored how TM can be used in cancer treatment, offering a comprehensive perspective on targeted and personalized approaches.

Keywords:  Cancer progression; Immune regulation; Microbial metabolites; Therapeutic interventions; Tumor microbiome

DOI:  https://doi.org/10.1186/s12943-025-02403-w
J Nanobiotechnology. 2025 Jul 15. 23(1): 514

Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions.

Zhiqiang Chen, Bo Wang, Jianwei Zheng, Chao Liu, Peijun Xu, Qianqian Zhou, Jiayong Li, Zijian Shi, Zhenduo Wang, Xuyan Wang, Shunjin Xia, Fangquan Xu, Xiaofeng Yao, Yu Wang, Xinwei Wang, Xiao Zhao, Nana Ma, Yu Ren, Keman Cheng, Xuan Zhou.

  The immunosuppressive tumor microenvironment (TME) critically undermines the efficacy of T cell-based tumor immunotherapy by impeding CD8+ T cell infiltration and cytotoxic function, primarily through tumor-associated macrophages (TAMs) and immune checkpoint molecules such as programmed death ligand 1 (PD-L1). Here, we present a multifunctional nanoplatform, IN@OMV-PDL1nb, designed to simultaneously inhibit TAM-derived immunosuppressive metabolite itaconic acid (ITA) by targeting immune-responsive gene 1 (IRG1) and block PD-L1 within the TME. Engineered outer membrane vesicles (OMVs) serve as precision delivery vehicles for the IRG1 inhibitor IRG1-IN-1 (IN) and as carriers for PD-L1 nanobody release, activated by matrix metalloproteinase-2 (MMP-2). IN@OMV-PDL1nb effectively inhibits IRG1 expression in TAMs, thus reducing the accumulation of ITA, restoring chemokines (CXCL9 and CXCL10) secretion, and enhancing CD8+ T cells infiltration within tumors. The released PD-L1 nanobody protects CD8+ T cells, preserving their tumoricidal activity. In murine tumor models, IN@OMV-PDL1nb significantly inhibited tumor growth, increased survival, and enhanced antigen presentation and T cell recruitment. Additionally, IN@OMV-PDL1nb induced robust adaptive immunity, facilitating antigen-specific immune memory that prevented tumor recurrence and metastasis. This dual-targeting approach offers a promising strategy to overcome TME-driven immunosuppression in tumor immunotherapy.

Keywords:  Immune checkpoint blockade; Outer membrane vesicles; Tumor immunotherapy; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12951-025-03507-7
Front Immunol. 2025 ;16 1506204

Relaxin-2-secreting CAR-T cells exhibit enhanced efficacy in stromal-rich xenograft tumors.

Hisataka Ogawa, Tomoya Ekawa, Yu Mizote, Takashi Akazawa, Hideaki Tahara.

   Introduction: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated notable efficacy in treating hematological malignancies. Although it has shown promise in the clinical management of solid tumors, poor outcomes in clinical trials highlight the challenges in developing therapies suitable for the distinct tumor microenvironment, which features a dense stroma composed of fibroblasts and extracellular matrix proteins, such as collagen, hyaluronan, proteoglycans, laminin, and elastin. These predominantly fibroblast-produced components create a barrier that can impede CAR-T cell infiltration into tumors, limiting their efficacy. CAR-T cells that migrate from tumor vessels into the stroma may become trapped before reaching tumor cells.
Methods: We engineered CAR-T cells to secrete relaxin-2 (RLN2), an antifibrotic peptide hormone. Known for its role in pregnancy, RLN2 facilitates the softening and remodeling of collagen in the cervix and pelvic ligaments, and also promotes collagen degradation in the tumor microenvironment by upregulating matrix metalloproteinase levels by binding to the receptor LGR7/RXFP1.
Results: In vitro studies revealed that cancer cells exposed to CAR-T cell-secreted RLN2 exhibited an increased expression and secretion of specific matrix metalloproteinases. In mouse xenograft models with abundant stromal content, RLN2-secreting CAR-T cells demonstrated significantly improved antitumor efficacy and infiltration into the tumor microenvironment compared to conventional CAR-T cells.
Discussion: RLN2 may enhance the antitumor activity of CAR-T cells against solid tumors by promoting their infiltration into the tumor microenvironment.

Keywords:  chimeric antigen receptor T cell; fibrosis; matrix metalloproteinase; pancreatic cancer; relaxin-2; solid tumor; tumor stroma

DOI:  https://doi.org/10.3389/fimmu.2025.1506204
Am J Transl Res. 2025 ;17(6): 4071-4086

Regulation of the tumor microenvironment by Traditional Chinese Medicine: current progress and future perspectives in oncology.

Zhaohong Wang, Fei Wang, Yongjun Zhang.

  The microenvironment in which tumor cells thrive constitutes a complex and dynamic system closely intertwined with tumors' occurrence, progression, metastasis, and drug resistance. As research in Traditional Chinese Medicine (TCM) for anticancer purposes advances, the holistic and multi-target regulatory principles of TCM have been proven highly suitable for modulating the tumor microenvironment (TME). Targeted therapy focusing on TME is poised to become a key area in future research on TCM's anticancer properties. This article provides an overview of TME characteristics and the current status of TCM's regulation of TME, offering insights into the application of TCM in anticancer research.

Keywords:  Chinese herbal medicine; Traditional Chinese Medicine; Tumor microenvironment; cancer; tumor

DOI:  https://doi.org/10.62347/NOAI4101
bioRxiv. 2025 May 10. pii: 2025.05.06.652455. [Epub ahead of print]

Targeting Siglec-10/α3β1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer.

Pratima Saini, Gauri Mirji, Sajad Ahmed Bhat, Kar Muthumani, Joel Cassel, Hsin-Yao Tang, Hiroaki Tateno, Rugang Zhang, Rahul S Shinde, Mohamed Abdel-Mohsen.

Tumor-associated macrophages (TAMs) in the tumor microenvironment exhibit impaired phagocytic activity, contributing to tumor progression. Here, we identify integrin α3β1, composed of ITGA3 and ITGB1 subunits, as a sialylated glycoprotein ligand for Siglec-10, an inhibitory receptor on TAMs in pancreatic ductal adenocarcinoma (PDAC). Mechanistically, the interaction between Siglec-10 on TAMs and α3β1 on PDAC cells suppresses macrophage-mediated phagocytosis, enabling immune evasion by PDAC. Consequently, disrupting Siglec-10 interactions with monoclonal antibodies significantly enhances macrophage phagocytosis of PDAC cells in vitro. In a PDAC xenograft mouse model engrafted with human macrophages, disrupting Siglec-10 interactions reduces tumor growth and activates the PI3K/MAPK/AP-1 signaling cascades in macrophages, enhancing their phagocytic capacity. These findings suggest that the interaction between Siglec-10 and integrin α3β1 is a key mediator of immune evasion by TAMs and highlight the therapeutic potential of targeting Siglec-10/α3β1 interactions to restore macrophage phagocytic capacity.

DOI: https://doi.org/10.1101/2025.05.06.652455
Math Biosci Eng. 2025 May 21. 22(7): 1653-1679

Optimal therapy schedule of chimeric antigen receptor (CAR) T cell immunotherapy.

Ruohan Li, Jinzhi Lei.

  Chimeric antigen receptor (CAR) T-cell therapy is a personalized immunotherapy approach in which a patient's T cells are genetically engineered to express synthetic receptors that specifically recognize and target tumor-associated antigens. This approach has demonstrated remarkable success in treating B-cell malignancies by directing CAR-T cells against the CD19 protein. However, treatment efficacy is influenced by the composition and distribution of CAR-T cell subsets administered to the patient. To investigate the impact of different CAR-T cell subtypes and infusion strategies, we developed a mathematical model that captures the dynamic interactions between tumor cells and CAR-T cells within the tumor immune microenvironment. Through computational simulations, we explored how varying the dosage and subtype proportions of infused CAR-T cells affects tumor dynamics and therapeutic outcomes. Our findings highlight the critical role of CAR-T cell subset composition in optimizing treatment efficacy, underscoring the necessity of precise dosing control and tailored infused strategies to maximize therapeutic success.

Keywords:   B-ALL ; CAR-T therapy ; mathematical model ; optimal therapy ; tumor-immune microenvironment

DOI:  https://doi.org/10.3934/mbe.2025061
J Immunother Cancer. 2025 Jul 15. pii: e011617. [Epub ahead of print]13(7):

Review: radiotherapy-mediated B cells within the TLS influence the tumor microenvironment.

Haihua Yang, Kuifei Chen, Yinan Meng, Ziran Chen, Yixiu Xu, Dandan Zhou, Suna Zhou, Xiaozhi Zhang.

  The tumor microenvironment (TME) is a diverse and intricate structure consisting of tumor cells, stromal cells, endothelial cells, and immune cells. It is characterized by the communication between tumor cells and both innate and adaptive immune cells. Tertiary lymphoid structures (TLS) are temporary abnormal collections of lymphoid tissues in which specialized immune responses against tumors can occur. B cells are crucial for the prognostic prediction of various cancers, particularly in response to immunotherapy. There are many types of B cells within the TME, including naive, terminally differentiated plasma, and memory B cells. Our focus was to understand the various types of B cells and how radiation therapy influences B cells in TLS. In this review, we discuss the notion that radiotherapy may alter the creation and function of B cells in TLS, which could result in a powerful and advanced form of cancer immunity.

Keywords:  B cell; RADIOTHERAPY; Tumor lymphoid structures - TLS; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-011617
bioRxiv. 2025 Jun 15. pii: 2025.06.10.658497. [Epub ahead of print]

Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands.

Sree H Kolli, Mitchell T McGinty, Audrey M Putelo, Cara N Hatzinger, Simona Bajgai, Mika K Poblete, Brandon Thompson, Tzu-Yu Feng, Francessca N Azar, Akshita Mirani, William A Petri, Stacey L Burgess, Melanie R Rutkowski.

Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While TLR5 signaling has previously been implicated in promoting myeloid cell recruitment to the ovarian TME, the upstream source of ligand and its systemic effects on hematopoiesis remain poorly understood(1,2). Here, we show that ovarian cancer disrupts gut barrier integrity, leading to systemic translocation of TLR5 ligands into the peritoneum, blood, and bone marrow. This translocation correlates with enhanced expansion of myeloid progenitors in the bone marrow of wild-type (WT) but not TLR5-deficient (TLR5 KO) mice, leading to enhanced accumulation of monocytes into the tumor microenvironment. Pharmacologic blockade of TLR5 in tumor-bearing mice alters the composition of tumor-associated myeloid populations, increasing the frequency of monocytes and CCR2-expressing macrophages In the bone marrow of tumor-bearing WT mice. In the bone marrow, blockade of TLR5 signaling led to expansion of granulocyte-monocyte progenitors (GMPs), a phenotype recapitulated in a competitive chimera model. In vitro, stimulation of WT bone marrow cells with purified TLR5 ligands led to enhanced colony formation and skewed differentiation toward granulocyte-macrophage lineages. These data reveal that chronic TLR5 signaling, driven by tumor-induced gut leakage, promotes expansion of myeloid cells within the bone marrow and is a host-intrinsic mechanism driving accumulation of immature monocytes and macrophages into the tumor microenvironment.

DOI: https://doi.org/10.1101/2025.06.10.658497
PLoS Biol. 2025 Jul 14. 23(7): e3003284

Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.

Yajing Qiu, Yihan Xu, Xinyuan Ding, Congcong Zhao, Hongcheng Cheng, Guideng Li.

Cancer cells and T cells engage in dynamic crosstalk within the tumor microenvironment (TME), shaping tumor progression and anti-tumor immunity. While cancer cells reprogram metabolism to support growth and immune evasion, T cells must adapt their metabolic states to maintain effector functions. Tumor-driven metabolic perturbations, such as nutrient depletion and accumulation of immunosuppressive metabolites, profoundly impair T cell function and fate. Conversely, metabolically reprogrammed T cells can modulate the TME and influence tumor growth. This reciprocal metabolic crosstalk represents both metabolic competition and intercellular communication, offering promising therapeutic targets.

DOI: https://doi.org/10.1371/journal.pbio.3003284
MedComm (2020). 2025 Jul;6(7): e70292

Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets.

Yutao Li, Qingyun Liu, Xilin Jing, Yuqi Wang, Xiaohua Jia, Xing Yang, Kezhong Chen.

  Cancer-associated fibroblasts (CAFs) are functionally diverse stromal regulators that orchestrate tumor progression, metastasis, and therapy resistance through dynamic crosstalk within the tumor microenvironment (TME). Recent advances in single-cell multiomics and spatial transcriptomics have identified conserved CAF subtypes with distinct molecular signatures, spatial distributions, and context-dependent roles, highlighting their dual capacity to promote immunosuppression or restrain tumor growth. However, therapeutic strategies struggle to reconcile this functional duality, hindering clinical translation. This review systematically categorizes CAF subtypes by origin, biomarkers, and TME-specific functions, focusing on their roles in chemoresistance, maintenance of stemness, and formation of immunosuppressive niches. We evaluate emerging targeting approaches, including selective depletion of tumor-promoting subsets (e.g., fibroblast activation protein+ CAFs), epigenetic reprogramming toward antitumor phenotypes, and inhibition of CXCL12/CXCR4 or transforming growth factor-beta signaling pathways. Spatial multiomics-driven combinatorial therapies, such as the synergistic use of CAFs and immune checkpoint inhibitors, are highlighted as strategies to overcome microenvironment-driven resistance. By integrating CAF biology with translational advances, this work provides a roadmap for developing subtype-specific biomarkers and precision stromal therapies, directly informing efforts to disrupt tumor-stroma coevolution. Key concepts include spatial transcriptomics, stromal reprogramming, and tumor-stroma coevolution, offering actionable insights for both mechanistic research and clinical innovation.

Keywords:  cancer‐associated fibroblasts; heterogeneity; pathogenesis; theranostic; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70292