bims-flamet 2025-12-21 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–12–21
nineteen papers selected by
Peio Azcoaga, Biodonostia HRI

The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.
Ambivalent roles of miRNAs in cancer development via modulating tumor-associated innate immune cells.
EGLN1 (PHD2) role in tumor microenvironment: insights for therapeutic targeting.
Crosstalk between tumor cells and tumor-associated macrophages mediated by extracellular vesicles: Research advances in remodeling the tumor microenvironment in colorectal cancer.
Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).
Tumor-associated macrophages in cancer: from mechanisms to application.
Extracellular Vesicles from Tumor-Associated Macrophages: Implications for Tumor Progression and Emerging Therapeutic Strategies.
Regulatory T cells in cancer: from immunosuppression to therapeutic targeting.
Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.
Macrophage Polarization in the Tumor Microenvironment of Hepatocellular Carcinoma: From Mechanistic Insights to Translational Therapies.
The role of CXCL5 in tumor microenvironment: Regulatory mechanisms and therapeutic potential.
SPP1 regulates tumor progression through modulation of signaling pathways and the tumor microenvironment.
Epigenetic regulation of the tumor microenvironment in lung cancer: mechanism insights and therapeutic prospects.
Cancer-associated fibroblasts in the tumor microenvironment: heterogeneity, crosstalk mechanisms, and therapeutic implications.
Potential strategies to improve the therapeutic efficacy of oncolytic viruses for cancer through T and NK cells targeting.
SMAD signaling in cancer: integrative roles in tumor progression, immune evasion, and therapeutic resistance.
Characteristics of the immune microenvironment, metabolic microenvironment, and gut microbiota in prostate cancer.
Cancer-associated fibroblasts in lymph node metastasis: Insights and therapeutic strategies.
Application and prospects of ultrasound combined with immunotherapy in cancer treatment of intensive care.

Cancer Res. 2025 Dec 15.

The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.

Jiin Lee, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong.

Lipid metabolism reprogramming modulates the tumor microenvironment (TME) and alters the function of immune cells, including tumor-infiltrating lymphocytes (TILs). While lipids can enhance general T cell activity, high lipid content in the TME may restrain the anti-tumor function of effector T cells and augment immunosuppression by regulatory T cells. In addition, lipid metabolism reprogramming greatly influences the crosstalk between TILs and other immune cells in the TME, including dendritic cells, macrophages, and myeloid-derived suppressor cells. By discussing potential therapeutic strategies to target lipid metabolism in TILs, along with combination approaches with chemo-immunotherapy, nanomedicine, and adoptive cell transfer therapy, we aim to lay the groundwork for advancing effective treatments for cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2568
Bioimpacts. 2025 ;15 31430

Ambivalent roles of miRNAs in cancer development via modulating tumor-associated innate immune cells.

Bahar Naseri, Amirhossein Mardi, Najibeh Shekari, Neda Shajari, Samin Abdolzadeh, Hossein Khorramdelazad, Amirhossein Hatami-Sadr, Milad Taghizadeh Anvar, Mohammad Reza Javan, Amirhossein Heibatollahi, Javad Masoumi, Farid Ghorbaninezhad, Behzad Baradaran.

  The tumor microenvironment (TME), comprising malignant and non-transformed cells like immune cells, endothelial cells, and cancer-associated fibroblasts, significantly affects tumor growth and progression. Tumor cells manipulate the TME by releasing chemokines and inhibitory cytokines, reprogramming surrounding cells to support their survival and evade immune detection. Innate immune cells within the TME play dual roles, either promoting or inhibiting tumor progression, impacting immunotherapy outcomes. Recent studies highlight the influence of innate immune cells in shaping the TME and the pivotal role of tumor-derived microRNAs (miRNAs) in modulating these cells. miRNAs regulate gene expression and enhance tumor immune evasion, angiogenesis, drug resistance, and invasion. Their tumor-specific expression patterns suggest potential as biomarkers and therapeutic targets. This study focuses on how miRNAs affect innate immune cells like macrophages, dendritic cells, myeloid-derived suppressor cells, and natural killer cells, contributing to immunosuppressive or immunogenic environments. Understanding miRNA-mediated interactions between cancer and immune cells opens new possibilities for improving targeted immunotherapy and advancing cancer treatments.

Keywords:  Biomarker; Cancer; Immunomodulation; Innate immune system; TME; miRNA

DOI:  https://doi.org/10.34172/bi.31430
Exp Mol Med. 2025 Dec 19.

EGLN1 (PHD2) role in tumor microenvironment: insights for therapeutic targeting.

Giulio Verna, Valentina Fantini, Alessandra Grieco, Alessia Ciarrocchi, Valentina Sancisi.

The tumor microenvironment (TME) is often hypoxic. EGLN1, which encodes the oxygen sensor PHD2, plays a crucial role not only in the survival of cancer cells but also in regulating other cell types that reside in the TME. In this Review, we explore the role of this protein in some of the key components of the TME, focusing on the functions of EGLN1/PHD2 in endothelial, stromal and immune cells. So far, the activity of EGLN1/PHD2 has been characterized in different cell types, albeit with controversial outcomes in different cancer settings. This Review aims to discuss the role of EGLN1/PHD2 in the TME and the strategies targeting this protein that might be used to hit tumors.

DOI: https://doi.org/10.1038/s12276-025-01602-1
Crit Rev Oncol Hematol. 2025 Dec 12. pii: S1040-8428(25)00467-6. [Epub ahead of print]218 105079

Crosstalk between tumor cells and tumor-associated macrophages mediated by extracellular vesicles: Research advances in remodeling the tumor microenvironment in colorectal cancer.

Dadi Shu, Zhaoming Chen, Baolin Li, Jing Wei, Jinbo Liu, Qiongying Hu.

  Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and ranks third in incidence among all cancer types. Among the treatment strategies for CRC, immunotherapy-particularly approaches targeting modulation of the tumor microenvironment (TME) to prevent immune escape-represents a key component. The interaction and influence between CRC cells and tumor-associated macrophages (TAMs) within the TME have been shown to be closely associated with immune escape and malignant progression in CRC. Among them, extracellular vesicles (EVs) derived from CRC cells (CRC-EVs) can be taken up by TAMs in the TME and regulate their polarization as well as the production of related bioactive substances. Conversely, EVs secreted by TAMs (TAMs-EVs) can be internalized by CRC cells, thereby promoting the malignant biological behaviors, including proliferation, metastasis, and resistance to radiotherapy and chemotherapy. In this review, we focus on the crosstalk between CRC cells and TAMs within the TME, summarizing and integrating current evidence on how CRC-EVs and TAMs-EVs contribute to TME remodeling and thereby influence CRC malignancy, while systematically outlining the cellular signaling pathways involved in this bidirectional communication.

Keywords:  Colorectal cancer; Crosstalk; Extracellular vesicles; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105079
Exp Cell Res. 2025 Dec 15. pii: S0014-4827(25)00467-7. [Epub ahead of print] 114867

Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).

Chou-Yi Hsu, Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mirza R Baig, Zahraa Khudhair, Saidmurodkhon Murtazaev, Pareshkumar N Patel, Subbulakshmi Ganesan, Vimal Arora, Sandeep Kumar Shukla, Priya Priyadarshini Nayak.

  Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the "reverse Warburg effect," producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.

Keywords:  CAF; Colorectal cancer; Immune cell; TAM; TME

DOI:  https://doi.org/10.1016/j.yexcr.2025.114867
Mol Biomed. 2025 Dec 19. 6(1): 145

Tumor-associated macrophages in cancer: from mechanisms to application.

Wan Tang, Xin Wang, Bing Han, Shu-Heng Jiang, Hongshi Cao.

  Tumor-associated macrophages (TAMs) are central constituents of the tumor microenvironment (TME), recruited from circulating monocytes through chemotactic signals, and they execute complex, multifaceted functions throughout tumor progression. Functionally heterogeneous, TAMs are broadly classified into distinct subtypes that display a dynamic duality, capable of shifting between tumor-suppressive and tumor-promoting states, though the pro-tumorigenic functions tend to dominate across multiple cancer types. The polarization of TAMs is modulated by diverse cytokines and signaling networks within the TME. Key pro-tumor mechanisms include activating proliferative signaling pathways, enhancing invasive and metastatic potential, establishing an immunosuppressive TME through immune cell interactions, and conferring therapy resistance. The spatial heterogeneity of TAMs further underscores the predictive relevance. Translational research increasingly focuses on TAM-targeting strategies such as inhibiting recruitment, depleting subsets, or reprogramming function. Emerging approaches, including nanomedicine-based targeting, macrophage-mediated therapies, and novel drug formulations, highlight the importance of combining conventional treatments with immune checkpoint inhibitors (ICIs). Such combinations help overcome therapeutic resistance and improve clinical outcomes. This review systematically summarizes recent advances in TAM biology and plasticity, biomarkers from single-cell and spatial analyses for distinguishing TAM subsets, and their prognostic relevance in immunotherapy. It also discusses TAM-targeting strategies and their synergistic potential with existing therapies. Together, these insights lay the foundation for next-generation cancer treatments that precisely target TAMs to overcome therapy resistance and improve patient survival.

Keywords:  Immune infiltration; Macrophage polarization; Prognostic prediction; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43556-025-00396-y
Exp Cell Res. 2025 Dec 11. pii: S0014-4827(25)00455-0. [Epub ahead of print] 114855

Extracellular Vesicles from Tumor-Associated Macrophages: Implications for Tumor Progression and Emerging Therapeutic Strategies.

Carolinne Souza Amorim, João Alfredo Moraes, Mariana Renovato Martins, Juliana Maria Motta.

  Extracellular vesicles (EVs) derived from tumor cells have been extensively explored over the past decades, as they represent a powerful means of communication that promotes tumor progression, including the formation of pre-metastatic niches and the consequent facilitation of successful metastatic dissemination. However, macrophages comprise a substantial population of non-tumoral cells within the tumor microenvironment and can either facilitate or inhibit tumor progression through the messages carried by their EVs. In this paper, we reviewed the literature on macrophage-derived EVs and their role in modulating tumor behavior, including development, metastasis, immune evasion, and chemoresistance. We begin by outlining the main categories of EVs and the subtypes of macrophage polarization, followed by a discussion of key aspects of macrophage-derived EVs across various tumor types. Finally, we examine emerging therapeutic strategies that utilize these EVs as potential tools in anticancer therapy.

Keywords:  anticancer therapy; extracellular vesicles; microRNA; tumor progression; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.yexcr.2025.114855
Front Immunol. 2025 ;16 1703211

Regulatory T cells in cancer: from immunosuppression to therapeutic targeting.

Paola Basurto-Olvera, Hector Serrano, Carmen Maldonado-Bernal.

  Regulatory T cells (Tregs) play a pivotal role in maintaining immune homeostasis; however, their presence in the tumor microenvironment contributes to immune evasion and cancer progression. The modulation of Tregs has emerged as a key strategy in immunotherapy, with approaches ranging from direct depletion to functional reprogramming. This review summarizes advances in Treg modulation through checkpoint blockade, selective depletion, and metabolic or epigenetic reprogramming. Additionally, we discuss the potential of Treg plasticity as a therapeutic avenue, emphasizing how shifts in Treg phenotype can enhance antitumor immunity. Furthermore, we highlight combinatory strategies, including radiotherapy, cytokine-based therapies, and metabolic targeting that reshape the immune landscape to potentiate cancer immunotherapy. Understanding the dynamic nature of Tregs cells and their modulation offers promising directions for enhancing therapeutic efficacy and overcoming resistance in several cancer types.

Keywords:  Treg depletion; Tregs cells; cancer; cellular plasticity; immune checkpoints; immunotherapy; leukemia; suppressor cells

DOI:  https://doi.org/10.3389/fimmu.2025.1703211
Int J Nanomedicine. 2025 ;20 14643-14665

Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.

Di Liu, Zhixiong Hao, Guangpeng He, Ye Huang.

  Regulatory T cells (Treg cells) play a crucial role in maintaining immune tolerance and regulating immune responses, especially in cancer, where their immunosuppressive function is highly significant. Treg cells accumulate in the tumor microenvironment (TME), interact with tumor cells and other immune cells, and suppress anti-tumor immunity through various mechanisms, including secretion of immunosuppressive cytokines, direct contact with target cells, and depletion of key nutrients and signaling molecules. Regulating Treg cells has become a novel approach for enhancing cancer immunotherapy. Extracellular vesicles (EVs) are small vesicles with a lipid bilayer membrane secreted by all cells and play an important role in tumor biology as communication mediators by transmitting proteins, RNA, and other bioactive molecules in TME. In the past years, an increasing amount of research has uncovered the effects of EVs on Treg in TME, greatly enriching our understanding of Treg in tumor progression. Additionally, due to the potential of EVs as "natural nanoparticles" for drug and gene delivery, targeting Treg via an EV-delivery system has become a hotspot. Therefore, we comprehensively summarized the updates on the effects of EVs on Treg in TME and EV-related therapy for tumor treatment.

Keywords:  extracellular vesicle; immunotherapy; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S562593
Cancer Control. 2025 Jan-Dec;32:32 10732748251406674

Macrophage Polarization in the Tumor Microenvironment of Hepatocellular Carcinoma: From Mechanistic Insights to Translational Therapies.

Xiaoqing Fu, Mingquan Pang, Zhixin Wang, Haijiu Wang.

  Background: Hepatocellular carcinoma (HCC) harbors a dynamic tumor microenvironment (TME) in which macrophages are highly abundant and plastic. Under physiological conditions, macrophages switch between inflammatory and resolution/tissue-repair programs to maintain homeostasis; however, during hepatocarcinogenesis these programs are reprogrammed into tumor-associated macrophage (TAM) states that foster immune suppression, angiogenesis, and tumor progression.Purpose: To summarize macrophage heterogeneity and polarization mechanisms in HCC, and to highlight omics-informed therapeutic opportunities for targeting TAMs and improving precision immunotherapy.Research Design: This review summarizes physiological macrophage polarization and the mechanistic basis of macrophage reprogramming in the hepatocellular carcinoma immune microenvironment, integrating evidence from recent advances in single-cell sequencing, multi-omics, and spatial transcriptomics, with a focus on macrophage subset diversity, key regulatory pathways governing polarization and function, and emerging macrophage-targeted interventions and biomarkers.Results: Recent single-cell and spatial multi-omics studies reveal substantial TAM heterogeneity and plasticity in HCC. Macrophage-targeted strategies-including TAM depletion, phenotypic reprogramming, and exosome-mediated drug delivery-show encouraging preclinical efficacy. Macrophage-associated prognostic models and biomarkers may support individualized immunotherapeutic approaches.Conclusions: Macrophage polarization in HCC represents a dynamic continuum that is essential for homeostasis but is co-opted by tumors to drive immunosuppression and tissue remodeling. Advances in single-cell and spatial multi-omics are redefining TAM subsets and actionable pathways, enabling more rational macrophage-targeted therapies. However, challenges remain in standardizing TAM definitions, identifying robust predictive biomarkers, minimizing off-target effects, and optimizing combinations with immunotherapy. Integrating longitudinal multi-omics with AI-based modeling may help predict macrophage state transitions, guide patient-specific regimens, and advance precision medicine in HCC.

Keywords:  Kupffer cells; exosomes; hepatocellular carcinoma; macrophage polarization; targeted therapy; tumor microenvironment; tumor stemness

DOI:  https://doi.org/10.1177/10732748251406674
Int J Cancer. 2025 Dec 18.

The role of CXCL5 in tumor microenvironment: Regulatory mechanisms and therapeutic potential.

Xiaoqi Yang, Huabing Kuang, Rong Sun, Lijuan Ye, Yao Chen, Zhixin Hu, Chengmin Deng, Xiaoqian Li, Longze Zhang, Yu Wang, Xin Tan, Shuai Liu, Yuguang Shen, Kaifeng Wu, Jingqiu Qu, Jie Wu.

  C-X-C motif chemokine ligand 5 (CXCL5), also known as epithelial neutrophil-activating peptide 78 (ENA-78), is a pivotal member of the ELR+ CXC chemokine family, characterized by a conserved glutamic acid-leucine-arginine motif. CXCL5 plays a central regulatory role in shaping the tumor immune microenvironment (TIME). Its expression is regulated by transcription factors (NF-κB, STAT3, SP1, p53), epigenetic modifications (DNA methylation, histone acetylation, microRNAs), and cytokines/growth factors (IL-1β, TNF, EGF). These regulatory mechanisms shape CXCL5 function in inflammation and cancer. CXCL5 interacts with diverse immune cells, including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), T lymphocytes, and myeloid-derived suppressor cells (MDSCs). These interactions establish an immunosuppressive microenvironment that drives tumor immune evasion, metastasis, and therapeutic resistance. Mechanistically, CXCL5 regulates the malignant phenotypes of tumor cells by activating signaling pathways including PI3K/AKT, JAK-STAT/NF-κB, and ERK/MSK1/Elk-1/snail. Recent preclinical studies highlight that blocking the CXCL5-CXCR2 axis reverses immunosuppression and improves immune checkpoint inhibitor efficacy. This review systematically maps the multidimensional regulatory network of CXCL5 in the TIME and summarizes its molecular interactions with immune cells. The therapeutic potential of targeting these pathways is also explored to inform novel immunotherapeutic combination strategies.

Keywords:  C‐X‐C motif chemokine ligand 5; chemokines; immune regulation; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1002/ijc.70296
Discov Oncol. 2025 Dec 14.

SPP1 regulates tumor progression through modulation of signaling pathways and the tumor microenvironment.

Yang Feng, Xuanbo Shao, Zhuo-Fan Xu, Penghao Liu, Huantong Wu, Yuanchen Cheng, Maoyang Qi, Hongfeng Meng, Boyan Zhang, Feng-Zeng Jian, Zan Chen, Wanru Duan.

  Secreted Phosphoprotein 1 (SPP1), also known as Osteopontin (OPN), is a phosphorylated glycoprotein that plays a crucial role in regulating various cellular functions and immune responses. Recent studies have highlighted SPP1's involvement in key physiological processes, including cell migration, proliferation, differentiation, and its significant impact on immune regulation and inflammatory responses. In the context of cancer, SPP1 is closely associated with tumor progression and prognosis. It contributes to tumorigenesis by promoting the formation of the tumor microenvironment (TME), influencing the behavior of tumor-associated cells, and enhancing tumor cell invasiveness and immune evasion. This review aims to provide a comprehensive analysis of SPP1's role in the development and progression of various cancers, highlighting its potential as a therapeutic target and biomarker for cancer management.

Keywords:  Osteopontin; SPP1; Tumor microenvironment; Tumor progression; Tumor-associated cells

DOI:  https://doi.org/10.1007/s12672-025-04273-6
Front Immunol. 2025 ;16 1697428

Epigenetic regulation of the tumor microenvironment in lung cancer: mechanism insights and therapeutic prospects.

Maoqin Yang, Xudong Lei, Dexiang Ren, Dakai Qin, Xiaojun Xia.

  Lung cancer, recognized as one of the most prevalent malignancies with the highest rates of incidence and mortality globally, presents a substantial challenge on a worldwide scale. This challenge is exacerbated by the disease's difficulty in early detection, a pronounced rate of metastasis, and resistance to treatment, all of which contribute to elevated mortality rates. The tumor microenvironment (TME) plays a critical role in the sustenance and advancement of various solid tumors, including lung cancer. The intricate composition of the TME facilitates tumor proliferation, metastatic spread, and therapeutic resistance by supplying metabolic resources, fostering angiogenesis, and enabling immune evasion. Nonetheless, the regulatory frameworks operating within the TME remain poorly understood. An increasing body of evidence suggests that epigenetic regulation-encompassing mechanisms such as DNA methylation, histone modification, and the action of non-coding RNAs-is pivotal in the initiation and progression of lung cancer. Furthermore, epigenetic modifications significantly influence the functional dynamics of the tumor microenvironment, thereby impacting intercellular interactions and cellular behaviors within the TME, which in turn affects the trajectory of disease progression. This article aims to present the most recent advancements in research concerning the epigenetic regulation of tumor cell interactions with the TME in the context of lung cancer biology. Additionally, it examines the current implications of epigenetic regulation within the tumor microenvironment and its influence on lung cancer behavior. We also investigate the potential relevance and emerging therapeutic avenues presented by epigenetic regulation in the clinical diagnosis and treatment of lung cancer, aspiring to propose novel strategies to address existing treatment challenges.

Keywords:  DNA methylation; histone modification; lung cancer; non-coding RNA; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1697428
Mol Cancer. 2025 Dec 18.

Cancer-associated fibroblasts in the tumor microenvironment: heterogeneity, crosstalk mechanisms, and therapeutic implications.

Ziyue Huang, Jie Chen, Tianyu Zhu, Jinxin Li, Ho Yin Ng, Yixiong Zhou, Xiang Gu, Shiqiong Xu, Renbing Jia.

  The tumor microenvironment (TME) is increasingly recognized as a critical modulator of the initiation, progression, metastasis, and therapeutic resistance of various cancers. Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the TME, play pivotal roles in these processes through their remarkable phenotypic and functional heterogeneity. Emerging evidence underscores the diversity in the origins, phenotypes, and functions of CAFs, highlighting their ability to adaptively influence tumor biology in a context-dependent manner. CAFs facilitate cancer malignancy via multiple interconnected mechanisms, including the secretion of soluble bioactive factors, the release of exosomes, the metabolic reprogramming of tumor cells, the remodeling of the extracellular matrix (ECM), and the modulation of the immune microenvironment. CAFs have emerged as attractive and viable therapeutic targets. Recent efforts have focused on developing therapies that disrupt the protumorigenic activities of CAFs or reprogram them toward tumor-suppressive phenotypes. Several of these strategies have shown promise and are advancing into clinical trials. In this review, we comprehensively discuss recent advancements in our understanding of the heterogeneity of CAFs, elucidate their multifaceted interactions within the TME, and explore novel therapeutic strategies targeting CAFs across various cancer types. Our review aims to foster the translation of preclinical insights into clinically effective interventions targeting CAFs.

Keywords:  Cancer-associated fibroblasts; Crosstalk; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02533-1
Crit Rev Oncol Hematol. 2025 Dec 14. pii: S1040-8428(25)00474-3. [Epub ahead of print]218 105086

Potential strategies to improve the therapeutic efficacy of oncolytic viruses for cancer through T and NK cells targeting.

Chuanjian Wu, Hanzhang Liu, Yujie Shi, Jie Tang, Rong Sun, Xudong Han, Yihui Fan.

  Oncolytic viruses (OVs) elicit potent tumor lysis and remodel the tumor microenvironment (TME) to activate adaptive and innate immunity, yet their efficacy depends critically on T and NK cell responses. Here, we review recent advances in the characterization and engineering of OVs to enhance lymphocyte-mediated tumor control. CD8⁺ cytotoxic T cells and CD4⁺ helper T cells drive durable antitumor immunity through OV-enhanced antigen presentation, memory formation, and modulation of Tregs, whereas T cell exhaustion and checkpoint interactions remain key barriers. Arming OVs with cytokines, chemokines, bispecific engagers, or metabolic modulators enhances effector T-cell expansion, infiltration, and cytotoxicity in solid tumors. In parallel, NK cells-whose efficacy is often limited by poor intratumoral activity and antiviral competition-are increasingly harnessed by OV platforms expressing immune stimulators or checkpoint modulators. Combination strategies with targeted therapies, checkpoint blockade, or adoptive NK/T cell transfer further potentiate therapeutic efficacy. Importantly, although OVs may inadvertently amplify dominant antiviral responses at the expense of antitumor activity, strategies incorporating tumor antigen encoding and TME reprogramming can overcome this limitation. Collectively, these findings underscore the central role of T and NK cells in OV-based immunotherapy and highlight rational arming and combination approaches to improve tumor control and long-term protection.

Keywords:  Cancer vaccine; Immune checkpoint inhibitors; Metabolism; Oncolutic virus; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105086
Cytokine. 2025 Dec 12. pii: S1043-4666(25)00237-6. [Epub ahead of print]198 157090

SMAD signaling in cancer: integrative roles in tumor progression, immune evasion, and therapeutic resistance.

Hai Zhao, Fan Yang, Jiaxin Yang, Sheng Yang.

  Transforming growth factor-beta (TGF-β)/SMAD signaling exerts pleiotropic effects in cancer, orchestrating epithelial-mesenchymal transition (EMT), immune evasion, stemness, and therapeutic resistance. While canonically regarded as tumor-suppressive, emerging data reposition SMAD proteins, particularly SMAD2, SMAD3, and SMAD4, as central effectors of pro-tumorigenic reprogramming in advanced malignancies. Here, we delineate the multifaceted contributions of SMAD signaling across tumor-intrinsic and microenvironmental contexts, highlighting post-translational regulation, immune remodeling, and crosstalk with non-coding RNAs. We show how SMADs mediate dynamic EMT programs, modulate innate and adaptive immune landscapes, and drive chemoresistance through transcriptional and metabolic rewiring. In the tumor microenvironment (TME), SMAD-driven axes involving macrophages, neutrophils, and CAFs reinforce immune suppression and metastasis. Moreover, engineering SMAD pathways in CAR-T and NK cells enhances immunotherapeutic efficacy. We also identify SMAD-based transcriptional and epigenetic signatures with prognostic and predictive utility across multiple tumor types. This integrative review provides a unified framework for understanding the SMAD signaling network as both a mechanistic driver and therapeutic vulnerability in cancer.

Keywords:  SMAD signaling; epithelial–mesenchymal transition; immune evasion; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cyto.2025.157090
Int J Surg. 2025 Dec 19.

Characteristics of the immune microenvironment, metabolic microenvironment, and gut microbiota in prostate cancer.

Fangmei Xie, Birong Zhou, Yinghui Hao, Shengjun Pan, Zeping Han, Xiaoyu Song, Wenfeng Luo, Ying Zhao, Jian Shen, Xin Ruo, Jinghui Fan, Jinhua He.

  The tumor microenvironment (TME) is a complex ecosystem comprising tumor cells and their surrounding components, such as stromal cells, extracellular matrix, blood vessels, and signaling molecules. It functions as the "soil" that sustains tumor survival and progression, critically influencing tumor growth, invasion, metastasis, and drug resistance. As a key component of the TME, the tumor immune microenvironment (TIME) refers specifically to the interactive network between tumor cells and the immune system. This interplay dictates whether tumors are recognized and eliminated by immune surveillance or succeed in evading immune detection.The gastrointestinal microecology (GM) system encompasses the gut microbiota and their respective habitats. Gut microbiota influence tumor progression through immune regulation, metabolic modulation, and genotoxic effects, thereby shaping therapeutic responses. Meanwhile, tumor cells employ diverse metabolic pathways to meet heightened bioenergetic and biosynthetic demands and to mitigate oxidative stress-processes essential for their proliferation and survival. These metabolic adaptations significantly shape TME characteristics, including nutrient availability, hypoxia, and the induction of immunosuppression.This review summarizes the roles of the immune microenvironment, metabolic microenvironment, and gut microbiota in the initiation, progression, and treatment of prostate cancer (PCa). It further illustrates how these three components interact to collectively regulate PCa development and therapeutic outcomes. By integrating recent advances in these areas, we aim to provide new insights into the molecular mechanisms of PCa pathogenesis and to inform comprehensive clinical strategies.

Keywords:  gut microbiota; prostate cancer; tumor immune microenvironment; tumor metabolic microenvironmen

DOI:  https://doi.org/10.1097/JS9.0000000000004449
Chin Med J (Engl). 2025 Nov 13.

Cancer-associated fibroblasts in lymph node metastasis: Insights and therapeutic strategies.

Jiawei Yuan, Rui Zhang, Zhimin Geng.

   ABSTRACT: Lymph node metastasis (LNM) represents a critical dissemination route for many malignancies, profoundly influencing patient prognosis through its role in driving disease progression and recurrence. This metastatic cascade involves tumor cell invasion into lymphatic structures, where the complex interactions within the tumor microenvironment (TME) facilitate further dissemination to distant sites. Among TME components, cancer-associated fibroblasts (CAFs) have emerged as pivotal regulators in disease progression and metastatic spread by orchestrating dynamic crosstalk between malignant cells and stromal networks. Mounting evidence highlights the multifaceted contributions of CAFs to LNM pathogenesis, particularly their capacity to prime metastatic niches and enable tumor cell intravasation into lymphatic vessels. This review systematically examines the molecular and functional mechanisms through which CAFs promote LNM, focusing on their dual roles in establishing pre-metastatic niches and facilitating lymphovascular invasion by tumor cells. By synthesizing recent advances in CAF biology and LNM pathophysiology, this review aims to deepen the mechanistic understanding of metastatic dissemination while identifying potential therapeutic opportunities for clinical translation.

Keywords:  Cancer-associated fibroblasts; Lymph node metastasis; Lymphovascular invasion; Pre-metastatic niche; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1097/CM9.0000000000003833
Front Immunol. 2025 ;16 1670527

Application and prospects of ultrasound combined with immunotherapy in cancer treatment of intensive care.

Yaping Wang, Cong Liu, Riley Lyu, Yan Zhang.

  The tumor microenvironment (TME) plays a crucial role in tumor initiation, progression, and metastasis, and immunotherapy targeting the TME has received increasing attention. However, single-agent immunotherapy has certain limitations and often requires combination with other adjuvant strategies to enhance therapeutic efficacy. Among these, ultrasound has emerged as a promising adjunct to cancer immunotherapy. By modulating the TME, ultrasound combined with immunotherapy shows great potential in enhancing antitumor responses. This review summarizes the application of various ultrasound modalities in enhancing antitumor immunity, improving the efficacy of immunotherapy, and regulating the TME. Ultrasound can amplify the therapeutic effects of immunotherapy through multiple mechanisms, including thermal effects, mechanical effects, microbubble cavitation, and sonodynamic therapy. Thermal effects induced by high-intensity focused ultrasound (HIFU) can destroy tumor tissues, releasing tumor antigens and heat shock proteins, thereby activating systemic immune responses. Mechanical approaches such as histotripsy can liquefy tumors without thermal damage, preserving antigenic structures and enhancing immune responses within the TME. Ultrasound-mediated microbubble cavitation increases vascular permeability, facilitating the delivery of immune cells and immune checkpoint inhibitors into tumor tissues and enhancing signal transduction to convert "cold" tumors into immune-active "hot" tumors. Sonodynamic therapy generates reactive oxygen species under ultrasound stimulation, inducing immunogenic cell death and reshaping the TME. Furthermore, this review outlines the research progress of ultrasound-immunotherapy combinations in various cancers, including lung cancer, breast cancer, and melanoma, demonstrating superior efficacy compared to immunotherapy alone. Ultrasound not only enhances antitumor immune effects but also enables real-time monitoring of tumor progression and immune modulation within the TME. Finally, the review discusses current challenges and future prospects. By systematically summarizing the types of ultrasound-assisted immunotherapy, their mechanisms within the TME, and recent advances in clinical applications, this article aims to provide a theoretical foundation and technical reference for developing ultrasound-immunotherapy strategies targeting the TME.

Keywords:  immunity; immunotherapy; tumor; tumor microenvironment; ultrasound; ultrasound-assisted immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1670527