bims-flamet 2025-04-27 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–04–27
33 papers selected by
Peio Azcoaga, Biodonostia HRI

Cancer Stem Cells and Tumor-Associated Macrophages: Interactions and Therapeutic Opportunities.
Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications.
SENP1-Sirt3 axis promotes cholesterol biosynthesis in tumor-associated macrophages to suppress anti-tumor immunity.
Crosstalk between exosomes and tumor-associated macrophages in hepatocellular carcinoma: implication for cancer progression and therapy.
Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
The role of tumor microenvironment and self-organization in cancer progression: Key insights for therapeutic development.
The roles of immune cells and non-immune cells in Pre-Metastatic Niche of Breast Cancer.
Enhancing antitumor immunity: the role of immune checkpoint inhibitors, anti-angiogenic therapy, and macrophage reprogramming.
The role of tumor-associated macrophages in HPV induced cervical cancer.
Cancer-associated fibroblasts as a potential novel liquid biopsy marker in cancer patients.
Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target.
Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity.
Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy.
Modeling Stromal Cells Inside the Tumor Microenvironment of Ovarian Cancer: In Vitro Generation of Cancer-Associated Fibroblast-Like Cells and Their Impact in a 3D Model.
Targeting PI3K Signaling to Overcome Tumor Immunosuppression: Synergistic Strategies to Enhance Cancer Vaccine Efficacy.
Exploring the Role of Cellular Interactions in the Colorectal Cancer Microenvironment.
The Tumor Immune Environment: Advances in the Cancer Immunotherapy Era.
[Research progress on the involvement of exosome-mediated intercellular communication in the remodeling and the regulation of invasion and metastasis in the hepatocellular tumor microenvironment].
Lipid metabolism involved in progression and drug resistance of breast cancer.
Exosomes as key mediators in immune and cancer cell interactions: insights in melanoma progression and therapy.
An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity.
Gemcitabine: immunomodulatory or immunosuppressive role in the tumor microenvironment.
Reprogramming and targeting of cholesterol metabolism in tumor-associated macrophages.
Macrophage Membrane-Coated Nanomedicine Enhances Cancer Immunotherapy by Activating Macrophages and T Cells.
Exosome-based immunotherapy in hepatocellular carcinoma.
Heteromulticellular Stromal Cells in Scaffold-free 3D Cultures of Epithelial Cancer Cells to Drive Invasion.
Modeling of cancer stem cells and the tumor microenvironment Via NT2/D1 cells to probe pathology and treatment for cancer and beyond.
Enhanced efficacy of dual chimeric antigen receptor-T cells targeting programmed death-ligand 1 and cancer-associated fibroblasts in colorectal cancer in vitro.
The role of CXC chemokines and receptors in breast cancer.
Designing Chimeric Antigen Receptors for Myeloid Immune Cells.
The important role of myeloid-derived suppressor cells: From hepatitis to liver cancer.
The role and research progress of serine metabolism in tumor cells.
Ferroptosis: a novel perspective on tumor immunotherapy.

Cancer Lett. 2025 Apr 22. pii: S0304-3835(25)00303-9. [Epub ahead of print] 217737

Cancer Stem Cells and Tumor-Associated Macrophages: Interactions and Therapeutic Opportunities.

Haitao Yuan, Yun Qiu, Zijie Mei, Jiaqing Liu, Lingna Wang, Kaiqing Zhang, Huicong Liu, Fangfang Zhu.

  Cancer stem cells (CSCs) depend on the tumor microenvironment (TME) to sustain their stem-like properties by recruiting monocytes and reprogramming them into tumor-associated macrophages (TAMs), which in turn promote tumor progression. This review explores CSC-TAM interactions, emphasizing how CSCs drive monocyte recruitment and TAM polarization. We discuss how TAMs enhance CSC stemness and niche maintenance through chemokines, cytokines, exosome-mediated miRNA transfer, direct interactions, and extracellular matrix (ECM) remodeling. Furthermore, we examine therapeutic strategies targeting TAMs, including inhibiting TAM differentiation, reprogramming TAM polarization, and leveraging immune checkpoint blockade and CAR-macrophage immunotherapy to improve cancer treatment outcomes.

Keywords:  CAR-macrophage therapy; Cancer stem cells; Cancer stemness maintenance; Chemokine/cytokine signaling; Exosomal miRNAs; Immune checkpoint blockade; Macrophage polarization; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.canlet.2025.217737
Front Oncol. 2025 ;15 1579054

Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications.

Francisco Alejandro Lagunas-Rangel.

  In many cancers, the tumor microenvironment is enriched with cholesterol due to increased biosynthesis and uptake by cancer cells, resulting in the accumulation of cholesterol, cholesterol esters, oxysterols and other metabolites with various functions. These molecules serve as structural components, energy sources and intracellular signaling mediators, while their toxic by-products are secreted to suppress anti-tumor immune activity and prevent lipid peroxidation that could induce cancer cell apoptosis. Immune cells in the tumor microenvironment also contribute to cholesterol dynamics. Tumor-associated macrophages (TAMs) release cholesterol to support tumor cell metabolism, while myeloid-derived suppressor cells (MDSCs) also release cholesterol and consume essential metabolites such as L-arginine, which impairs T-cell proliferation and activation. Elevated cholesterol in dendritic cells impairs migration and tumor antigen presentation and, in lymphocytes, favors the development of a regulatory T cells (Treg) phenotype and inhibits the release of antitumor cytokines, further weakening the immune response. These findings suggest that targeting cholesterol metabolism is a promising strategy for cancer treatment, improving the efficacy of immune checkpoint blockade (ICB) therapies. In this manuscript, the molecular mechanisms underlying the effects of cholesterol on the tumor immune landscape are reviewed and the potential of cholesterol-lowering drugs to enhance antitumor immune responses is explored.

Keywords:  LDLR; LXR; SREBP2; myeloid-derived suppressor cells; statins; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fonc.2025.1579054
Cancer Lett. 2025 Apr 17. pii: S0304-3835(25)00294-0. [Epub ahead of print] 217728

SENP1-Sirt3 axis promotes cholesterol biosynthesis in tumor-associated macrophages to suppress anti-tumor immunity.

Guoyuan Peng, Xinyu Yang, Jianli He, Mingming Zhang, Kexin Liu, Jun Tu, Hongsheng Tan, Innocent Agida, Wei Zhou, Jinke Cheng, Tianshi Wang.

  Tumor-associated macrophages (TAMs) play a multifaceted role in the tumor microenvironment, notably by suppressing antitumor immune responses through immunosuppressive mechanisms. TAMs secrete a range of cytokines that simultaneously inhibit T cell function and foster a microenvironment that supports tumor progression and dissemination. Our study has delved into the intricate relationship between the metabolic reprogramming of TAMs and their impact on tumor progression. Mitochondrial metabolic reprogramming mediated by the SENP1-Sirt3 axis altered the dynamics and activity of tumor-infiltrating immune cells, including macrophages and CD8+ T lymphocytes. SENP1-Sirt3 axis increases the level of acetyl-CoA in macrophage mitochondria, which in turn promotes cholesterol biosynthesis in macrophages. The upregulation of cholesterol synthesis is a key factor in driving macrophage polarization towards the immunosuppressive M2 phenotype, which in turn supports tumor development. Notably, increased cholesterol levels contributed to a reduction in the number and activity of CD8+ T cells, which are essential for mounting an effective immune response against cancer cells. These findings suggest that targeting cholesterol biosynthesis in TAMs may be a promising strategy for cancer immunotherapy. SIGNIFICANCE: Activation of the SENP1-Sirt3 axis initiates mitochondrial metabolic reprogramming in tumor-associated macrophages (TAMs), leading to enhanced cholesterol and acetyl-CoA production, M2 macrophage polarization, and impaired CD8+ T cell anti-tumor responses.

Keywords:  SENP1-Sirt3 axis; acetyl-CoA; cholesterol biosynthesis; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.canlet.2025.217728
Front Immunol. 2025 ;16 1512480

Crosstalk between exosomes and tumor-associated macrophages in hepatocellular carcinoma: implication for cancer progression and therapy.

Ying Xu, Linyue Xu, Qiuyan Chen, Can Zou, Ju Huang, Limei Zhang.

  Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, represents a significant cause of cancer-related mortality. While our understanding of its pathogenesis is comparatively comprehensive, the influence of the tumor microenvironment (TME) on its progression warrants additional investigation. Tumor-associated macrophages (TAMs) have significant impacts on cancer cell proliferation, migration, invasion, and immune response, facilitating a complex interaction within the TME. Exosomes, which measure between 30 and 150 nanometers in size, are categorized into small extracellular vesicles, secreted by a wide range of eukaryotic cells. They can transfer biological molecules including proteins, non-coding RNAs, and lipids, which mediates the intercellular communication within the TME. Emerging evidence has revealed that exosomes regulate macrophage polarization, thus impacting cancer progression and immune responses within the TME of HCC. Moreover, TAM-derived exosomes also play crucial roles in malignant transformation, which hold immense potential for cancer therapy. In this review, we elaborate on the crosstalk between exosomes and TAMs within TME during HCC development. Moreover, we delve into the feasible treatment approaches for exosomes in cancer therapy and emphasize the limitations and challenges for the translation of exosomes derived from TAMs into clinical courses for cancer therapy, which may provide new perspectives on further ameliorations of therapeutic regimes based on exosomes to advance their clinical applications.

Keywords:  exosome; hepatocellular carcinoma; immunotherapy; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3389/fimmu.2025.1512480
Nat Immunol. 2025 Apr 22.

Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.

Mojdeh Shakiba, David A Tuveson.

Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.

DOI: https://doi.org/10.1038/s41590-025-02134-6
Bioimpacts. 2025 ;15 30713

The role of tumor microenvironment and self-organization in cancer progression: Key insights for therapeutic development.

Milad Asadi, Venus Zafari, Sanam Sadeghi-Mohammadi, Dariush Shanehbandi, Ufuk Mert, Zahra Soleimani, Ayşe Caner, Habib Zarredar.


Introduction: The tumor microenvironment (TME) plays a pivotal role in cancer progression, influencing tumor initiation, growth, invasion, metastasis, and response to therapies. This study explores the dynamic interactions within the TME, particularly focusing on self-organization-a process by which tumor cells and their microenvironment reciprocally shape one another, leading to cancer progression and resistance. Understanding these interactions can reveal new prognostic markers and therapeutic targets within the TME, such as extracellular matrix (ECM) components, immune cells, and cytokine signaling pathways.
Methods: A comprehensive search method was employed to investigate the current academic literature on TME, particularly focusing on self-organization in the context of cancer progression and resistance across the PubMed, Google Scholar, and Science Direct databases.
Results: Recent studies suggest that therapies that disrupt TME self-organization could improve patient outcomes by defeating drug resistance and increasing the effectiveness of conventional therapy. Additionally, this research highlights the essential of understanding the biophysical properties of the TME, like cytoskeletal alterations, in the development of more effective malignancy therapy.
Conclusion: This review indicated that targeting the ECM and immune cells within the TME can improve therapy effectiveness. Also, by focusing on TME self-organization, we can recognize new therapeutic plans to defeat drug resistance.

Keywords:  Extracellular matrix; Invasion; Metastasis; Self-organization; Tumor microenvironment

DOI:  https://doi.org/10.34172/bi.30713
Crit Rev Oncol Hematol. 2025 Apr 22. pii: S1040-8428(25)00132-5. [Epub ahead of print] 104744

The roles of immune cells and non-immune cells in Pre-Metastatic Niche of Breast Cancer.

Qiao Zheng, Tiecheng Zhou, Dejiao Yao.

  Distant metastasis is a pivotal and important event in patients with breast cancer, and inhibition of metastasis has always been the focus of clinical research. Recent advances have established that the metastasis of breast cancer is exacerbated not only by cancer cells and the tumor microenvironment but also by the pre-metastatic niche (PMN). Primary tumor secretory factors, immune cells including bone marrow-derived cells mobilized by tumors and non-immune cells within the local matrix microenvironment of the host are three key factors for PMN formation. This article reviews the roles of bone marrow-derived cells, lymphocytes, fibroblasts, endothelial cells, epithelial cells and cancer stem cells in the establishment of PMN before metastasis to further understand the metastasis mechanism of breast cancer and to explore clues for the inhibition of distant metastasis. Different cells play distinct but important roles in the establishment of the PMN and the induction of breast cancer metastasis. The interaction between different cells and tumor cells determines whether CTCs can be attached, survive and proliferate to promote distant metastasis.

Keywords:  Bone marrow-derived cells (BMDCs); Breast cancer (BC); Circulating tumor cells (CTCs); Fibroblasts; Pre-metastatic niche (PMN)

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104744
Front Oncol. 2025 ;15 1526407

Enhancing antitumor immunity: the role of immune checkpoint inhibitors, anti-angiogenic therapy, and macrophage reprogramming.

Chong Zhang, Hua Wang, Xinying Li, Yuxin Jiang, Guoping Sun, Hanqing Yu.

  Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Keywords:  ICIS; angiogenesis; biomarkers; combination therapy; macrophage

DOI:  https://doi.org/10.3389/fonc.2025.1526407
Front Immunol. 2025 ;16 1586806

The role of tumor-associated macrophages in HPV induced cervical cancer.

Zeping Chen, Binzhu Zhao.

  Human papillomavirus (HPV), a double-stranded DNA virus linked to various malignancies, poses a significant global public health challenge. In cervical cancer, persistent infection with high-risk HPV genotypes, particularly HPV-16 and HPV-18, initiates immune evasion mechanisms within the tumor microenvironment. The polarization of tumor-associated macrophages (TAMs) from M1 to M2 phenotypes promotes cervical carcinogenesis, metastasis, and therapeutic resistance via establishing an immunosuppressive microenvironment. This review provides a comprehensive overview of HPV-induced immune evasion pathways, including MHC downregulation, T-cell impairment, regulatory T cell induction, and cGAS-STING pathway inhibition. Furthermore, describe the pivotal role of TAMs in cervical cancer progression, focusing on their phenotypic plasticity, pro-tumoral functions, and potential as therapeutic targets. By elucidating these cellular and molecular dynamics, this review aims to support advanced research. Targeting TAM polarization through immunotherapies and nanomedicine-based strategies represents a promising strategy for enhancing patient outcomes.

Keywords:  HPV; TAM recruitment; cervical cancer; diagnosis; immune response; macrophage; vaccine

DOI:  https://doi.org/10.3389/fimmu.2025.1586806
J Exp Clin Cancer Res. 2025 Apr 21. 44(1): 127

Cancer-associated fibroblasts as a potential novel liquid biopsy marker in cancer patients.

Franziska Weber, Kim-Lea Reese, Klaus Pantel, Daniel J Smit.

  Cancer-associated fibroblasts (CAFs) are tissue residing cells within the tumor microenvironment (TME). Stromal CAFs have been shown to be associated with poor prognosis and tumor progression in several solid tumor entities. Although the molecular mechanisms are not fully understood yet, a critical role within the TME through direct interaction with the tumor cells as well as other cells has been proposed. While most studies on CAFs focus on stromal CAFs, recent reports highlight the possibility of detecting circulating CAFs (cCAFs) in the blood. In contrast to invasive tissue biopsies for stromal CAF characterization, liquid biopsy allows a minimally invasive isolation of cCAFs. Furthermore, liquid biopsy methods could enable continuous monitoring of cCAFs in cancer patients and therefore may present a novel biomarker for solid tumors. In this work, we present an overview of cCAF studies currently available and summarize the liquid biopsy techniques for cCAF isolation and detection. Moreover, the future research directions in the emerging field are highlighted and the potential applications of cCAFs as novel biomarkers for solid tumor patients discussed.

Keywords:  Blood-based biomarkers; Circulating cancer-associated fibroblasts; Liquid biopsy; cCAFs

DOI:  https://doi.org/10.1186/s13046-025-03387-7
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00402-4. [Epub ahead of print]44(5): 115631

Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target.

Guorong Zhang, Hanzhi Yu, Jingjing Liu, Ge Dong, Zhigang Cai.

  Leucine-rich repeat containing 25 (LRRC25), a type I membrane protein, is specifically expressed in myeloid cells including neutrophils and macrophages. The anti-inflammatory role of LRRC25 was suggested in a few pathogenic models. However, its role in cancer immunity has not been interrogated. Here, we demonstrate that LRRC25 is robustly expressed in tumor-associated macrophages (TAMs). Lrrc25 deficiency in the tumor microenvironment (TME) suppresses growth of multiple murine tumor models by reprogramming TAMs toward an anti-tumor phenotype and thereby enhancing infiltration and activation of CD8+ T cells. The Nox2-ROS-Nlrp3-Il1β pathway is elevated in Lrrc25-deficient TAMs. Furthermore, a human myeloid cell line or mice with loss of Lrrc25 appear normal, indicating that LRRC25 is a safe immune target. Our results suggest that as an unappreciated immune checkpoint for tumor immunotherapy, the myeloid-specific membrane protein LRRC25 orchestrates the activity of TAMs via the canonical Nlrp3-IL1β inflammatory pathway and influences CD8+ T cell chemotaxis to the TME.

Keywords:  CP: Cancer; CP: Immunology; LRRC25; cancer immunotherapy; membrane protein; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115631
Science. 2025 Apr 25. 388(6745): eadr3026

Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity.

David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Qiang Liu, Kazukuni Hayashi, Bo Yu, Ryan Lee, Catherine Zhang, Xiuli An, Jayakumar Rajadas, Nathan E Reticker-Flynn, Erinn B Rankin, Edgar G Engleman.

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

DOI: https://doi.org/10.1126/science.adr3026
Oncogene. 2025 Apr 21.

Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy.

Jinghui Liu, Xinyi Wang, Daheng He, Hamed Maasoumyhaghighi, Mansoureh Nouri, Meng Wu, Jia Peng, Xiongjian Rao, Ruixin Wang, Sai Wu, Jianlin Wang, Nigel Brooks, Neil Pegg, Kris Frese, Zhiguo Li, Xiaoqi Liu.

Blockade of immune checkpoints, such as programmed death-ligand 1 (PD-L1), has shown promise in cancer treatment; however, clinical response remains limited in many cancer types. Our previous research demonstrated that p300/CBP mediates the acetylation of the PD-L1 promoter, regulating PD-L1 expression. In this study, we further investigated the role of the p300/CBP bromodomain in regulating PD-L1 expression using CCS1477, a selective bromodomain inhibitor developed by our team. We found that the p300/CBP bromodomain is essential for H3K27 acetylation at PD-L1 enhancers. Inhibiting this modification significantly reduced enhancer activity and PD-L1 transcription, including exosomal PD-L1, which has been implicated as key contributors to resistance against PD-L1 blockade therapy in various cancers. Furthermore, CCS1477 treatment resulted in a marked reduction of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) by inhibiting key cytokines such as IL6, CSF1, and CSF2, which are crucial for MDSC differentiation and recruitment. By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes.

DOI: https://doi.org/10.1038/s41388-025-03417-w
MedComm (2020). 2025 May;6(5): e70172

Modeling Stromal Cells Inside the Tumor Microenvironment of Ovarian Cancer: In Vitro Generation of Cancer-Associated Fibroblast-Like Cells and Their Impact in a 3D Model.

Jacopo Romoli, Paola Chiodelli, Patrizia Bonassi Signoroni, Elsa Vertua, Clarissa Ferrari, Elisabetta Giuzzi, Alice Paini, Elisa Scalvini, Andrea Papait, Francesca Romana Stefani, Antonietta Rosa Silini, Ornella Parolini.

  The tumor microenvironment (TME) is the combination of cells and factors that promotes tumor progression, and cancer-associated fibroblasts (CAFs) are a key component within TME. CAF originates from various stromal cells and is activated by factors such as transforming growth factor-beta (TGF-β) secreted by tumor cells, favoring chemoresistance and metastasis. Recent publications have underlined plasticity and heterogeneity and their strong contribution to the reactive stroma within the TME. Our study aimed to replicate the TME's structure by creating a 3D in vitro model of ovarian cancer (OC). By incorporating diverse tumor and stromal cells, we simulated a physiologically relevant environment for studying CAF-like cell behavior within tumor spheroids in a context-dependent manner. CAF-like cells were generated by exposing human dermal fibroblasts to OC cell line conditioned media in the presence or absence of TGF-β. Herein, we found that different stimuli induce the generation of heterogeneous populations of CAF-like cells. Notably, we observed the ability of CAF-like cells to shape the intratumoral architecture and to contribute to functional changes in tumor cell behavior. This study highlights the importance of precise assessment of CAF for potential therapeutic interventions and further provides a reliable model for investigating novel therapeutic targets in OC.

Keywords:  3D model; cancer‐associated fibroblast; ovarian cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70172
Vaccines (Basel). 2025 Mar 10. pii: 292. [Epub ahead of print]13(3):

Targeting PI3K Signaling to Overcome Tumor Immunosuppression: Synergistic Strategies to Enhance Cancer Vaccine Efficacy.

Ran Cui, Zhongxiang Luo, Xialin Zhang, Xinlin Yu, Gang Yuan, Xingming Li, Fei Xie, Ou Jiang.

  Phosphoinositide 3-kinases (PI3Ks), members of the lipid kinase family, play a significant role in modulating immune cell functions, including activation, proliferation, and differentiation. Recent studies have identified the PI3K signaling pathway as a key regulator in tumor biology and the immune microenvironment. This pathway enhances the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), contributing to an immunosuppressive tumor microenvironment that impairs the effectiveness of cancer vaccines and immunotherapies. The present study explores PI3K isoforms, particularly p110γ and p110δ, and their associated signaling pathways. The therapeutic potential of selective PI3K inhibitors and their capacity to act synergistically with immunization strategies are analyzed. Targeting the PI3K signaling pathway represents a promising approach to counteract tumor-induced immune suppression and improve the efficacy of immune checkpoint inhibitors and vaccines, ultimately leading to better clinical outcomes.

Keywords:  PI3K; cancer; vaccine

DOI:  https://doi.org/10.3390/vaccines13030292
J Immunol Res. 2025 ;2025 4109934

Exploring the Role of Cellular Interactions in the Colorectal Cancer Microenvironment.

Jiadai Tang, Liuhan Chen, Xin Shen, Tingrong Xia, Zhengting Li, Xiaoying Chai, Yao Huang, Shaoqiong Yang, Xinjun Peng, Junbo Lai, Rui Li, Lin Xie.

  Colorectal cancer (CRC) stands as one of the tumors with globally high incidence and mortality rates. In recent years, researchers have extensively explored the role of the tumor immune microenvironment (TME) in CRC, highlighting the crucial influence of immune cell populations in driving tumor progression and shaping therapeutic outcomes. The TME encompasses an array of cellular and noncellular constituents, spanning tumor cells, immune cells, myeloid cells, and tumor-associated fibroblasts, among others. However, the cellular composition within the TME is highly dynamic, evolving throughout different stages of tumor progression. These shifts in cell subpopulation proportions lead to a gradual transition in the immune response, shifting from an early antitumor growth to a late-stage environment that supports tumor survival. Therefore, it is crucial to further investigate and understand the complex interactions among the various cell populations within the TME. In this review, we explore the key cellular components of varying origins, subpopulations with shared origins, and noncellular elements within the CRC TME, examining their interconnections and critical considerations for developing personalized and precise immunotherapy strategies.

Keywords:  cellular and noncellular constituents; cellular and noncellular functions; colorectal cancer; tumor immune microenvironment

DOI:  https://doi.org/10.1155/jimr/4109934
Methods Mol Biol. 2025 ;2926 15-34

The Tumor Immune Environment: Advances in the Cancer Immunotherapy Era.

Adit Ben-Baruch.

  For over the last hundred years, the scientific community has demonstrated much interest in the roles of the immune system in regulating tumor progression. Extensive research that was performed in this context has revealed that mechanisms of acquired immunity can be highly potent in eradicating cancer cells, if given the right conditions to do so. Basic and clinical studies have paved the way toward the design of sophisticated modalities that improve the ability of T cells to efficiently recognize cancer antigens (when expressed by the tumor cells) and to expand thereafter; alongside developing procedures that prevent immune suppression caused by inhibitory immune checkpoints, these approaches offer cancer patients improved immunotherapies, which increase remission and prolong survival. The current chapter provides a summary of key aspects relevant to such immunotherapies, including the following: (1) cancer vaccines that enhance cancer antigen presentation; (2) adoptive cell transfer (ACT)-based therapies, like tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor expressing T cells (CAR-T cells); and (3) immune checkpoint blockades (ICBs) that downregulate the extent of immune suppression mediated by inhibitory immune checkpoint molecules, like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands, primarily PD-L1 (and also PD-L2). These treatments have revolutionized the immunotherapy field, demonstrating the strong power of acquired immunity in preventing tumor growth and progression, giving much hope to cancer patients worldwide.

Keywords:  Adoptive cell therapy; Cancer vaccines; Chimeric antigen receptor T cells; Immune checkpoint blockades; Immune surveillance; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/978-1-0716-4542-0_2
Zhonghua Gan Zang Bing Za Zhi. 2025 Mar 20. 33(3): 280-286

[Research progress on the involvement of exosome-mediated intercellular communication in the remodeling and the regulation of invasion and metastasis in the hepatocellular tumor microenvironment].

K Q Zhong, W H Ren, T Li.

Hepatocellular carcinoma (referred to as liver cancer) tumor microenvironment (TMEs) is a dynamic network system composed of stromal cells, such as liver cancer cells, immune cells, vascular endothelial cells, adipocytes, fibroblasts, and various cytokines that play an important role in the invasion and metastasis of liver cancer. In recent years, there has been an increasing attention on the role of exosomes in the remodeling and the regulation of invasion and metastasis in liver cancer TMEs. Exosomes, as a natural carrier, mediate intercellular communication between liver cancer cells and with other stromal cells, playing an important role in the formation of immunosuppressive TMEs, angiogenesis and hypoxia tolerance, and the coordination of heterogeneity among liver cancer cells. This review summarizes the composition of liver cancer TMEs, the biological functions of exosomes, and the role and mechanism of exosome-mediated liver cancer TMEs between liver cancer cells and other stromal cells, with a focus on exosome involvement in the remodeling and regulating invasion and metastasis in liver cancer TMEs. Simultaneously, it also introduces and explores the application of exosomes in the diagnosis and treatment of liver cancer, with the hope that in-depth research and elucidation of the mechanisms of exosome involvement in the remodeling and regulation of invasion and metastasis in liver cancer TMEs will provide feasible research ideas for novel biological markers and drug delivery carriers.

DOI: https://doi.org/10.3760/cma.j.cn501113-20230920-00114
Genes Dis. 2025 Jul;12(4): 101376

Lipid metabolism involved in progression and drug resistance of breast cancer.

Wenxiang Fu, Aijun Sun, Huijuan Dai.

  Breast cancer is the most common malignant tumor threatening women's health. Alteration in lipid metabolism plays an important role in the occurrence and development of many diseases, including breast cancer. The uptake, synthesis, and catabolism of lipids in breast cancer cells are significantly altered, among which the metabolism of fatty acids, cholesterols, sphingolipids, and glycolipids are most significantly changed. The growth, progression, metastasis, and drug resistance of breast cancer cells are tightly correlated with the increased uptake and biosynthesis of fatty acids and cholesterols and the up-regulation of fatty acid oxidation. Cholesterol and its metabolite 27-hydroxycholesterol promote the progression of breast cancer in a variety of ways. The alteration of lipid metabolism could promote the epithelial-mesenchymal transition of breast cancer cells and lead to changes in the tumor immune microenvironment that are conducive to the survival of cancer cells. While the accumulation of ceramide in cancer cells shows an inhibitory effect on breast cancer. This review focuses on lipid metabolism and elaborates on the research progress of the correlation between different lipid metabolism and the growth, progression, and drug resistance of breast cancer.

Keywords:  Breast cancer; Ceramide; Cholesterol; Drug resistance; Fatty acids; Lipid metabolism; Tumor progression

DOI:  https://doi.org/10.1016/j.gendis.2024.101376
Arch Dermatol Res. 2025 Apr 19. 317(1): 729

Exosomes as key mediators in immune and cancer cell interactions: insights in melanoma progression and therapy.

Chou-Yi Hsu, Harish C Chandramoorthy, Jaafaru Sani Mohammed, Shaker Al-Hasnaawei, Mohammed Yaqob, Mayank Kundlas, Krishnakumar Samikan, Samir Sahoo, S K Sunori, Zainab Ahmed Abbas.

  Exosomes (30-150 nm) are small extracellular vesicles that are secreted by cells into the extracellular environment and are known to mediate cell-to-cell communication. Exosomes contain proteins, lipids, and RNA molecules in relative abundance, capable of modifying the activity of target cells. Melanoma-derived exosomes (MEXs) promote the transfer of oncogenic signals and immunosuppressive factors into immune cells, resulting in a bias of the immune response towards tumor-promoting processes. MEXs could suppress the activation and proliferation of T cells and dendritic cells and induce differentiation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). They can induce apoptosis of antigen-specific CD8 + T cells and promote the transfer of tumor antigens, resulting in immune evasion. Specifically, MEXs can shuttle cytokines like interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) to immune cells or express programmed death-ligand 1 (PD-L1 or CD274), creating an immune-suppressive microenvironment that promotes tumorigenesis. Since exosomes preferentially accumulate in melanoma tissues, this targeted delivery could enhance the bioavailability of treatments while limiting side effects. Here, we review the molecular composition of melanoma-derived exosomes, their mechanisms of action, and their potential as therapeutic targets or biomarkers in melanoma. The summarizations of these mechanisms to appropriately influence exosome-mediated interactions could yield new tactics to elicit anti-melanoma immunity or augment the therapeutic effects of current therapies.

Keywords:  Communication; Exosome; Immune cell; MEX; Melanoma

DOI:  https://doi.org/10.1007/s00403-025-04237-4
Neoplasia. 2025 Apr 21. pii: S1476-5586(25)00040-5. [Epub ahead of print]65 101161

An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity.

Li Xiao, Rong Hu, Wei Chen, Jie Gao, Youbo Zhao, Zuli Wang, Guangshi Du, Yishen Tian, Laijun Lai, Lu Liu, Min Su.

  Tumors exploit immune checkpoints to evade immune responses. Therefore, targeting these checkpoints has become a key strategy in cancer immunotherapy. In this study, we have developed a novel immune checkpoint inhibitor (ICI) targeting the B7 family-related molecule BTN2A2. The human BTN2A2 protein, which was highly expressed in some tumor tissues and activated antigen-presenting cells (APCs), can inhibit T cell activation and proliferation. The anti-BTN2A2 monoclonal antibody (mAb) can neutralize the inhibitory effect of BTN2A2 on T cells. In mouse models of pancreatic cancer and glioma, compared to the control group, the anti-BTN2A2 treatment group exhibited tumor shrinkage of 35.8 % (P < 0.05) and 51.2 % (P < 0.01), respectively, along with increased CD8+ tumor-infiltrating lymphocytes (TILs) by 1.7-fold (P < 0.001) and 2.2-fold (P < 0.001), respectively. In addition, anti-BTN2A2 mAb also increased the infiltration of B cells, M1 macrophages, and the expression of inflammatory cytokines in T cells, while reducing the infiltration of M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Thus, anti-hBTN2A2 mAb normalizes the immunodeficient tumor microenvironment (TME) and inhibits tumor growth. Our results suggest that targeting the BTN2A2 immune checkpoint may represent a novel strategy for cancer treatment, especially in immunosuppressive 'cold' tumors.

Keywords:  B7 family; BTN2A2; Immune checkpoint inhibitor (ICI); T cells; Tumor immunity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.neo.2025.101161
Front Immunol. 2025 ;16 1536428

Gemcitabine: immunomodulatory or immunosuppressive role in the tumor microenvironment.

Mahnaz Nemati, Chou-Yi Hsu, Deepak Nathiya, M Ravi Kumar, Enwa Felix Oghenemaro, Muthena Kariem, Parjinder Kaur, Deepak Bhanot, Ahmed Hjazi, Tayebeh Azam Saedi.

  Gemcitabine (GEM), a nucleoside analog chemotherapy agent, has been widely used in the treatment of various cancers. In recent years, there has been growing interest in understanding the immunomodulatory or immunosuppressive effects of GEM. The immunomodulatory roles of GEM could influence the anti-tumor immune responses via several mechanisms, such as modulation of antigen presentation, cytokine production, and immune cell population. Furthermore, there is evidence that GEM enhances the therapeutic efficacy of immunotherapies, including oncolytic viruses, immune checkpoint inhibitors, CAR T-cells, and therapeutic vaccines. On the other hand, accumulating evidence also proposed that GEM may act as an immunosuppressive agent within the tumor microenvironment, resulting in immune evasion of tumor cells and tumor growth. These paradoxical roles of GEM in modifying immune responses highlight the complexity of GEM interaction with immune cells and responses within the tumor microenvironment. This review aims to provide an overview of the immunomodulatory and immunosuppressive effects of GEM within the tumor microenvironment and how GEM affects the efficacy of cancer immunotherapy.

Keywords:  cancer; gemcitabine; immunomodulatory; immunosuppressive; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1536428
J Mater Chem B. 2025 Apr 23.

Reprogramming and targeting of cholesterol metabolism in tumor-associated macrophages.

Qiaoluo Ma, Ying Zhu, Dongya Zhang, Xiaohan Su, Can Jiang, Yuzhu Zhang, Xingting Zhang, Na Han, Guang Shu, Gang Yin, Maonan Wang.

Cholesterol, as a major component of cell membranes, is closely related to the metabolic regulation of cells and organisms; tumor-associated macrophages play an important push role in tumor progression. We know that tumor-associated macrophages are polarized from macrophages, and the abnormalities of cholesterol metabolism that may be induced during their polarization are worth discussing. This manuscript focuses on metabolic abnormalities in tumor-associated macrophages, and first provides a basic summary of the regulatory mechanisms of abnormal macrophage polarization. Subsequently, it comprehensively describes the features of abnormal glucose, lipid and cholesterol metabolism in TAMs as well as the different regulatory pathways. Then, the paper also discusses the link between abnormal cholesterol metabolism in TAMs and tumors, chronic diseases and aging. Finally, the paper summarizes cancer therapeutic strategies targeting cholesterol metabolism that are already in clinical trials, as well as nanomaterials capable of targeting cholesterol metabolism that are in the research stage, in the hope of providing value for the design of targeting materials. Overall, elucidating metabolic abnormalities in tumor-associated macrophages, particularly cholesterol metabolism, could provide assistance in tumor therapy and the design of targeted drugs.

DOI: https://doi.org/10.1039/d5tb00236b
Mol Pharm. 2025 Apr 23.

Macrophage Membrane-Coated Nanomedicine Enhances Cancer Immunotherapy by Activating Macrophages and T Cells.

Yongmei Zhao, Lulu Pei, Baolin Liu, Zehao Mao, Yingyi Niu, Siqi Li, Meiqing Yang, Wenqian Liu, Hongde Hai, Yunyao Luo, Tianqing Liu.

  Cancer immunotherapy has transformed malignancy treatment, but the tumor microenvironment (TME) presents significant obstacles. PD-1 blockade therapy, while widely used, faces issues such as resistance, adverse events, and limited predictive biomarkers. Therefore, novel therapeutic strategies are needed to enhance their efficacy and safety. Tumor-associated macrophages (TAMs), often exhibiting an anti-inflammatory M2 phenotype, contribute to poor prognoses and treatment resistance. Targeting TAMs to repolarize them to a pro-inflammatory M1 state can alleviate immunosuppression and enhance T cell-mediated antitumor responses. TMP195, a class IIa histone deacetylase inhibitor, has shown potential in reprogramming TAMs and synergizing with anti-PD-1 antibodies, although clinical application challenges exist. This study aimed to enhance the PD-1 blockade immunotherapy effectiveness by activating tumor-killing macrophages and T cells using biomimetic nanomedicines. A novel macrophage cell membrane-coated PLGA nanoparticle loaded with small molecule inhibitor, TMP195 (M1@PLGA-PEG-TMP195), was designed, prepared, and characterized. This macrophage membrane-coated PLGA nanoparticle delivery system had good drug loading and cancer cell targeting ability. This approach repolarized TAMs to M1 phenotypes and, combined with PD-1 inhibitors, achieved synergistic cancer treatment effects, improving therapeutic efficacy and inhibiting breast cancer growth and metastasis.

Keywords:  TMP195; anti-PD-1; immunotherapy; macrophage cell membrane; tumor-associated macrophages

DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00950
Clin Exp Med. 2025 Apr 24. 25(1): 127

Exosome-based immunotherapy in hepatocellular carcinoma.

Hong Liu, GuoWei Wang, ZhaoYi Li, XianTu Zhang, WeiDong Zhang, Xia Zhang, Fang Liu, Jing Gao.

  Hepatocellular carcinoma (HCC) is a significant global health concern and ranks as the third leading cause of cancer-associated mortality. Systemic therapy faces the emergence of resistance, which hinders the clinical benefits. Recent evidence suggests that exosomes, measuring between 30 and 150 nm in size, which impact the antitumor immune responses, making them a promising candidate for cancer immunotherapy. Owing to their unique physical and chemical characteristics, exosomes can be tailored and engineered for a range of therapeutic objectives. In the present review, we outline the immunomodulatory functions of exosomes in the tumor microenvironment (TME) of HCC, aiming to decipher the underlying mechanisms of exosomes in remodeling suppressive TME. Moreover, we provide detailed and intuitive resource for leveraging the potential of exosomes in immunotherapy, presenting valuable strategies to improve and optimize HCC treatment. Despite the huge therapeutic potential of exosomes, significant challenges persist, including the need for standardization in exosome production, optimization of cargo loading techniques, and the assurance of safety and effectiveness in clinical applications. Addressing these challenges may pave the way for exosome-based immunotherapy for HCC patients.

Keywords:  Exosomes; Hepatocellular carcinoma; Immunotherapy; Tumor microenvironment; Tumor vaccine

DOI:  https://doi.org/10.1007/s10238-025-01659-2
J Vis Exp. 2025 Apr 04.

Heteromulticellular Stromal Cells in Scaffold-free 3D Cultures of Epithelial Cancer Cells to Drive Invasion.

Elizabeth Ortiz, Kyaw Hsu Thway, Gabriela Ortiz-Soto, Paulina Yao, Jonathan A Kelber.

Breast cancer is the second leading cause of cancer-related death among women in the U.S. Organoid models of solid tumors have been shown to faithfully recapitulate aspects of cancer progression such as proliferation and invasion. Although patient-derived organoids and patient-derived xenograft organoids are pathophysiologically relevant, they are costly to propagate, difficult to manipulate, and comprised primarily of the most proliferative cell types within the tumor microenvironment (TME). These limitations prevent their use for elucidating cellular mechanisms of disease progression that depend upon tumor-associated stromal cells which are found within the TME and known to contribute to metastasis and therapy resistance. Here, we report on methods for cultivating epithelial-stromal multicellular 3D cultures. The advantages of these methods include a cost-effective system for rapidly generating organoid-like 3D cultures within scaffold-free environments that can be used to track invasion at single-cell resolution within hydrogel scaffolds. Specifically, we demonstrate how to generate these heteromulticellular 3D cultures using BT-474 breast cancer cells in combination with fibroblasts (BJ-5ta), monocyte-like cells (THP-1), and/or endothelial cells (EA.hy926). Additionally, differential fluorescent labeling of cell populations enables time-lapse microscopy to define 3D culture assembly and invasion dynamics. Notably, the addition of any two stromal cell combinations to 3D cultures of BT-474 cells significantly reduces circularity of the 3D cultures, consistent with the presence of organoid-like or secondary spheroid structures. In tracker dye experiments, fibroblasts and endothelial cells co-localize in the peripheral organoid-like protrusions and are spatially segregated from the primary BT-474 spheroid. Finally, heteromulticellular 3D cultures of BT-474 cells have increased hydrogel invasion capacity. Since we observed these protrusive structures in heteromulticellular 3D cultures of both non-tumorigenic and tumorigenic breast epithelial cells, this work provides an efficient and reproducible method for generating organoid-like 3D cultures in a scaffold-free environment for subsequent analyses of phenotypes associated with solid tumor progression.

DOI: https://doi.org/10.3791/67902
Discov Oncol. 2025 Apr 24. 16(1): 605

Modeling of cancer stem cells and the tumor microenvironment Via NT2/D1 cells to probe pathology and treatment for cancer and beyond.

Mia C Borlongan, Thomas Rodriguez, Napasiri Putthanbut, Hongbin Wang, Jea-Young Lee.

   INTRODUCTION: Unique from the other tumor cells, tumorigenic cancer stem cells (CSCs) manifest as a subpopulation of cells within the tumor that exhibit genetic and phenotypic features and signaling processes, which escape traditional anti-oncogenic treatments, thereby triggering metastases and relapses of cancers. Critical to cancer biology is the crosstalk between CSCs and tumor microenvironment (TME), implicating a CSC-based cancer immunotherapy. Cognizant of CSCs' significant role in cancer pathology and treatment, finding a biological model that recapitulates CSCs and TME may allow a better understanding of tumor onset and progression for testing CSC-based therapies. In this review paper, we examined the CSC and TME characteristics of the human embryonal carcinoma NTERA-2 clonal cell line called NTERA-2 cl.D1 or NT2/D1 cells and discussed their potential utility for research and development of treatments for cancer and central nervous system (CNS) disorders.
METHODS: To probe our hypotheses that NT2/D1 cells display CSC and TME properties key to tumor development, which can serve as a screening platform to test cancer and CNS therapeutics, we conducted a literature review over a 10-year period (2014-2024), focusing on PUBMED and Science Direct published articles on cellular models of cancer, with emphasis on milestone research discoveries on NT2/D1 cells relevant to CSCs and TME. We categorized the studies under pre-clinical and clinical investigations in supporting the existence of CSC and TME features in NT2/D1 cells and providing a laboratory-to-clinic translational basis for cancer and CNS therapeutics.
CONCLUSIONS: NT2/D1 cells stand as a feasible biological model that recapitulates the crosstalk of CSCs and TME, which may critically contribute to our understanding of cancer and CNS biology and therapeutics. Designing therapeutics against CSCs' distinct self-renewal and differentiation capacities within the TME opens new avenues for treating cancers and CNS disorders.

Keywords:  Cancer stem cells; Cancer treatment; NT2 cells; NT2/D1 cells; Stem cell therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02158-2
Cytojournal. 2025 ;22 29

Enhanced efficacy of dual chimeric antigen receptor-T cells targeting programmed death-ligand 1 and cancer-associated fibroblasts in colorectal cancer in vitro.

Yang Gao, CanJing Luo, Hua Yang, QiaoJin Xie, HaoJie He, JiaWei Li, JiDong Miao.

   Objective: Colorectal cancer (CRC) presents significant treatment challenges, including immune evasion and tumor microenvironment (TME) suppression. Chimeric antigen receptor (CAR) T-cell therapy has shown promise in hematologic malignancies, but its effectiveness against solid tumors is hampered by the detrimental effects of the TME. This article aims to explore the potential of bispecific CAR T cells targeting programmed death-ligand 1 (PD-L1) and cancer-associated fibroblasts (CAFs) in CRC treatment.
Material and Methods: Dual-targeted CAR-T cells against PD-L1 and CAF were engineered using the GV400 lentiviral vector. Programmed death-1 (PD-1)/nanobody (Nb) and fibroblast activation protein (FAP)/Nb-encoding lentiviral vectors were generated, and CAR T cells were produced through a three-plasmid system in 293T cells. Human peripheral blood mononuclear cells (PBMCs) were separated, transduced with these vectors, and then expanded. Functional characterization of CAR-T cells was performed through enzyme-linked immunosorbent assay (ELISA), Western blot analysis, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, and cell counting kit-8 (CCK-8) assay. Migration and invasion assays were conducted using Transwell chambers to assess the ability of FAP-PD-1/Nb CAR-T cells to migrate toward tumor cells and invade the extracellular matrix.
Results: We developed dual-targeted CAR-T cells incorporating PD-L1 and CAF Nbs, which continuously secreted PD-1/Nb. Western blot confirmed PD-1/Nb expression in PD-1/Nb and FAP-PD-1/Nb CAR-T cells, with no expression in the untreated (UTD) group (P < 0.01). Flow cytometry showed a significantly higher cluster of differentiation (CD)25 and CD69 expression in FAP-PD-1/Nb CAR-T cells upon stimulation with FAP-positive target cells compared with the other groups (P < 0.01). TUNEL, flow cytometry, and CCK-8 assays revealed that FAP-PD-1/Nb CAR-T cells exhibited superior cytotoxicity and proliferation inhibition against FAP-positive HCT116 cells (P < 0.01). ELISA demonstrated increased interferon-gamma and tumor necrosis factor-alpha levels and reduced interleukin-10 (P < 0.01), suggesting enhanced cytokine modulation and antitumor immunity. Compared with single-target CAR-T cells and UTD, FAP-PD-1/Nb CAR-T cells showed notably enhanced Matrigel penetration and invasion (P < 0.01). Safety tests confirmed minimal cytotoxicity to normal PBMCs, indicating favorable safety.
Conclusion: This study successfully developed dual-targeted CAR-T cells against PD-L1 and CAF and demonstrated their superior antitumor activity and immunomodulatory effects on CRC treatment. This novel therapeutic strategy was established using CAR T-cell technology for the treatment of CRC.

Keywords:  Chimeric antigen receptor-T cells; Colorectal cancer; Fibroblast activation protein; Programmed death-ligand 1; Tumor microenvironment

DOI:  https://doi.org/10.25259/Cytojournal_245_2024
Clin Exp Med. 2025 Apr 25. 25(1): 128

The role of CXC chemokines and receptors in breast cancer.

Mahdi Masrour, Aysan Moeinafshar, Amirhossein Poopak, Sepideh Razi, Nima Rezaei.

  CXC chemokines are a class of cytokines possessing chemotactic properties. Studies indicate that CXC chemokines exhibit dysregulation in miscellaneous cancer categories and are significantly associated with the advancement of tumors. Breast cancer is a commonly diagnosed and fatal cancer among the female population. Breast cancer pathogenesis and progression involve various mechanisms, including invasion, metastasis, angiogenesis, and inflammation. Chemokines and their receptors are involved in all of these processes. The CXC chemokine receptors (CXCRs) and their related ligands have attracted considerable attention due to their multifaceted functions in facilitating and controlling tumor proliferation. CXCRs are expressed by both cancer cells and immune cells, and they play a crucial role in regulating the tumor microenvironment and the immune response. This review aims to assess the potential of CXCRs and CXC chemokines as therapeutic targets or biomarkers for personalized therapy. Additionally, it provides an overview of the current understanding of the expression, function, and prognostic relevance of CXCRs in breast cancer. Furthermore, the challenges and potential prospects pertaining to CXCR investigation in breast cancer are deliberated.

Keywords:  Breast cancer; CXC chemokines; CXC receptors; CXCRs; chemokines

DOI:  https://doi.org/10.1007/s10238-025-01662-7
J Cancer Biol Res. 2024 ;pii: 1144. [Epub ahead of print]11(1):

Designing Chimeric Antigen Receptors for Myeloid Immune Cells.

Willem Buys, Elias T Zambidis.

Chimeric antigen receptor (CAR) myeloid cells are a promising potential alternative to CAR T-cells for solid tumor therapies. Myeloid CAR therapies have been tested in preclinical studies by either transferring established CD3-based T-cell CARs into myeloid cells, or by designing myeloid-specific signaling domains. While ITAM-based myeloid receptors (e.g., Fc-receptors) were often outperformed by classic CD3ζ-designs, toll-interleukin-1 receptor (TIR) and Mer receptor tyrosine kinase (MerTK) have shown promise for improving myeloid-specific cell activation. Addition of CD147 to stimulate matrix-metalloproteinase production and of cytokine genes (e.g. interferon γ) may further improve the efficacy of CAR-myeloid cells in the tumor immune microenvironment. While most work focused on CAR monocytes and macrophages, CAR-DC cells are also being studied as tumor vaccines in preclinical and early clinical phases. Lastly, even though CAR neutrophils are disadvantaged by a short lifespan, they could become viable by transfusing them as undifferentiated myeloid progenitors instead of effector cells. Here, we summarize the status of preclinical and clinical research on different CAR myeloid strategies, compare receptor designs, outline gaps in knowledge, conflicting results, and approaches for future preclinical studies that will allow translation of these technologies to the clinic.

Keywords: CAR Myeloid cells; Chimeric antigen receptor (CAR); Dendritic cell; Monocyte/Macrophage; Neutrophil
Biochim Biophys Acta Rev Cancer. 2025 Apr 20. pii: S0304-419X(25)00071-X. [Epub ahead of print]1880(3): 189329

The important role of myeloid-derived suppressor cells: From hepatitis to liver cancer.

Siwen Li, Jiaqian Zhang, Wang Wei, Zhicheng Zhang, Wenjie Huang, Limin Xia.

  Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.

Keywords:  Clinical therapy; Hepatocellular carcinoma (HCC); Liver disease; Myeloid-derived suppressor cells (MDSCs); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.bbcan.2025.189329
Front Oncol. 2025 ;15 1509662

The role and research progress of serine metabolism in tumor cells.

Hanning Lyu, Shuchang Bao, Lingyun Cai, Mengke Wang, Yuxin Liu, Yang Sun, Xiaoyang Hu.

  Serine is crucial for tumor initiation, progression, and adaptive immunity. Metabolic pathways for serine synthesis, acquisition, and utilization in tumors and tumor-associated cells are influenced by various physiological factors and the tumor microenvironment, leading to metabolic reprogramming and amplification. Excessive serine metabolism promotes abnormal macromolecule biosynthesis, mitochondrial dysfunction, and epigenetic modifications, driving malignant transformation, proliferation, metastasis, immune suppression, and drug resistance in tumor cells. Restricting dietary serine intake or reducing the expression of serine synthetic enzymes can effectively slow tumor growth and extend patient survival. Consequently, targeting serine metabolism has emerged as a novel and promising research focus in cancer research. This paper reviews serine metabolic pathways and their roles in tumor development. It summarizes the influencing factors of serine metabolism. The article explores the significance of serine synthesis and metabolizing enzymes, along with related biomarkers, in tumor diagnosis and treatment, providing new insights for developing targeted therapies that modulate serine metabolism in cancer.

Keywords:  cancer; one-carbon metabolism; serine catabolism; serine metabolism; the immunosuppressive microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1509662
Front Immunol. 2025 ;16 1524711

Ferroptosis: a novel perspective on tumor immunotherapy.

Yuan Xu, Mingpai Ge, Yuqing Xu, Kai Yin.

  Ferroptosis is a novel form of programmed cell death characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. The execution of ferroptosis is intricately linked to both iron and lipid metabolism. Intriguingly, iron and lipid metabolism are also pivotal for maintaining the physiological function of immune cells. Research has revealed that ferroptosis can potentiate the immunogenicity of tumor cells and engage in intricate interactions with immune cells. Certain ferroptosis inducers have the capacity to augment the efficacy of immunotherapy by modulating the tumor immune microenvironment. Ferroptosis holds immense potential in cancer immunotherapy and is anticipated to emerge as a novel therapeutic target in the future landscape of cancer treatment. In this review, we primarily delineate the ferroptosis signaling pathways and metabolic processes pertinent to immune cells, and further summarize the roles of ferroptosis in tumor-infiltrating immune cells. Ultimately, we anticipate further elucidation of the mechanisms of ferroptosis in immunotherapy and envision that strategies targeting ferroptosis and immunotherapy will be expeditiously applied in clinical oncology practice.

Keywords:  ferroptosis; immune cell; immunotherapy; metabolism; tumor immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1524711