bims-flamet 2025-05-04 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–05–04
28 papers selected by
Peio Azcoaga, Biodonostia HRI

Mesothelial and immune cells interplay in the tumor microenvironment.
Immunocytes in the tumor microenvironment: recent updates and interconnections.
PD-1 regulates the anti-tumor immune function of macrophages through JAK2-STAT3 signaling pathway in colorectal cancer tumor microenvironment.
Role of Tumor-Associated Macrophages in Breast Cancer Immunotherapy.
Advancing immunotherapy with innovations in CAR-M engineering for cancer treatment.
Angiogenesis and immune microenvironment in triple-negative breast cancer: Targeted therapy.
Research progress on the regulatory role of lactate and lactylation in tumor microenvironment.
Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy.
Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.
Nano-strategies for Targeting Tumor-Associated Macrophages in Cancer immunotherapy.
EZH2 regulatory roles in cancer immunity and immunotherapy.
Macrophage-derived exosomes in cancer: a double-edged sword with therapeutic potential.
Targeting nerve growth factor: an Achilles' heel for tumors?
Serine metabolism in tumor progression and immunotherapy.
CAF-mediated tumor vascularization: From mechanistic insights to targeted therapies.
The role and clinical significance of tumor-associated macrophages in the epithelial-mesenchymal transition of lung cancer.
Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor.
Cholinergic T cells revitalize the tumor immune microenvironment: TIME to ChAT.
The Dynamic Interplay between Melanoma Cells and CAFs: Implications Drug Resistance and Immune Evasion and Possible Therapeutics.
[Regulation of myeloid-derived suppressor cells by glutamate].
Unraveling the breast cancer tumor microenvironment: crucial factors influencing natural killer cell function and therapeutic strategies.
Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.
Single-Cell Profiling Reveals Global Immune Responses During the Progression of Murine Epidermal Neoplasms.
Chimeric antigen receptor NK cells for breast cancer immunotherapy.
Role of Neutrophils in Anti-Tumor Activity: Characteristics and Mechanisms of Action.
Vascularized tumor-on-a-chip to investigate immunosuppression of CAR-T cells.
Cytokine-based immunotherapy for gastric cancer: targeting inflammation for tumor control.
Dual cytokine-engineered macrophages rejuvenate the tumor microenvironment and enhance anti-PD-1 therapy in renal cell carcinoma.

Trends Mol Med. 2025 Apr 29. pii: S1471-4914(25)00086-3. [Epub ahead of print]

Mesothelial and immune cells interplay in the tumor microenvironment.

Rong Sheng, Yujia Yin, Xipeng Wang.

  Mesothelial cells (MCs) constitute a dynamic mesothelium in which their numerous crucial functions synergistically interact with other cells to maintain serosal integrity and homeostasis. Previous studies have confirmed the crucial role of interactions between MCs and tumor cells in tumorigenesis and progression in the tumor microenvironment (TME). However, recent research has found that MCs can induce an immunosuppressive microenvironment by secreting various cytokines, chemokines, and exosomes which recruit immunosuppressive cells or interact with immune cells, thus contributing to tumor progression. This review primarily examines the immunoregulatory role of MCs in the TME of mesothelioma and metastatic pleural and peritoneal carcinomas. It also explores the potential mechanisms by which these interactions induce immunosuppression and their impact on tumor growth and therapy.

Keywords:  cancer-associated mesothelial cells; immune suppression; mesothelial cells; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2025.03.014
Front Immunol. 2025 ;16 1517959

Immunocytes in the tumor microenvironment: recent updates and interconnections.

Jiyao Yu, Li Fu, Rui Wu, Linyi Che, Guodong Liu, Qinwen Ran, Zhiwei Xia, Xisong Liang, Guanjian Zhao.

  The tumor microenvironment (TME) is a complex, dynamic ecosystem where tumor cells interact with diverse immune and stromal cell types. This review provides an overview of the TME's evolving composition, emphasizing its transition from an early pro-inflammatory, immune-promoting state to a later immunosuppressive milieu characterized by metabolic reprogramming and hypoxia. It highlights the dual roles of key immunocytes-including T lymphocytes, natural killer cells, macrophages, dendritic cells, and myeloid-derived suppressor cells-which can either inhibit or support tumor progression based on their phenotypic polarization and local metabolic conditions. The article further elucidates mechanisms of immune cell plasticity, such as the M1/M2 macrophage switch and the balance between effector T cells and regulatory T cells, underscoring their impact on tumor growth and metastasis. Additionally, emerging therapeutic strategies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T and NK cell therapies, as well as approaches targeting metabolic pathways, are discussed as promising avenues to reinvigorate antitumor immunity. By integrating recent molecular insights and clinical advancements, the review underscores the importance of deciphering the interplay between immunocytes and the TME to develop more effective cancer immunotherapies.

Keywords:  cancer immunity; immune checkpoints; immunosuppression; lymphocytes; myeloid cells

DOI:  https://doi.org/10.3389/fimmu.2025.1517959
J Transl Med. 2025 May 02. 23(1): 502

PD-1 regulates the anti-tumor immune function of macrophages through JAK2-STAT3 signaling pathway in colorectal cancer tumor microenvironment.

Han Jiang, Jingjing Pang, Tengyue Li, Atitso Akofala, Xiaoxi Zhou, Changhua Yi, Shangwei Ning, Xu Gao, Yu Qiao, Jiayuan Kou.

   BACKGROUND: Tumor-associated macrophages (TAMs), as key immune components of the TME, play a pivotal role in tumor progression by fostering an immunosuppressive environment. Programmed death 1 (PD-1), a critical immune checkpoint molecule predominantly expressed on T cells, mediates immune suppression by binding to programmed death-ligand 1 (PD-L1) on tumor cells within the tumor microenvironment (TME). Emerging evidence reveals that TAMs also express PD-1, however, the expression and functional regulatory mechanisms of PD-1 on TAM remain poorly understood.
METHODS: In this study, we combined bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to investigate the association between PD-1 expression on macrophages and patient prognosis, while also uncovering the molecular mechanisms by which PD-1 regulates macrophage function. To further investigate the role of PD-1 in macrophage activity, we established a fluorescence-labeled tumor-bearing mouse model using CT26 cells, a murine colorectal cancer cell line, to evaluate the relationship between PD-1 expression on TAMs and their phagocytic activity as well as other functions. Additionally, to mimic the TME in vitro, we cultured bone marrow-derived macrophages (BMDMs) with CT26-conditioned medium (CT26-CM).
RESULTS: Our results suggest that PD-1 expression on TAMs drives macrophage polarization toward an M2-like phenotype, suppresses their phagocytic activity, inhibits the synthesis of interferon-γ (IFN-γ) signaling molecules, and ultimately promotes tumor progression. Mechanistically, we demonstrated that PD-1 regulates the synthesis of IFN-γ signaling molecules and the polarization of M2-type macrophages in BMDMs through the JAK2-STAT3 signaling pathway. Overall, our study demonstrates that PD-1 expression on TAMs facilitates the formation of an immunosuppressive microenvironment, ultimately accelerating tumor progression.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Anti-tumor; Bone marrow-derived macrophages; JAK2-STAT3 signaling pathway; Programmed death-1; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12967-025-06469-4
Front Biosci (Landmark Ed). 2025 Apr 23. 30(4): 26995

Role of Tumor-Associated Macrophages in Breast Cancer Immunotherapy.

Yan He, Quan Liu, Zhihao Luo, Qian Hu, Li Wang, Zifen Guo.

  Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.

Keywords:  breast cancer; immunotherapy; tumor-associated macrophages

DOI:  https://doi.org/10.31083/FBL26995
Int Immunopharmacol. 2025 Apr 26. pii: S1567-5769(25)00710-6. [Epub ahead of print]156 114720

Advancing immunotherapy with innovations in CAR-M engineering for cancer treatment.

Chaelin Lee, Chaerin Kwak, Minhyun Choi, Ahban Kim, Seongjin Kim, Inmoo Rhee.

  Chimeric antigen receptor macrophage (CAR-M) therapy is emerging as a promising immunotherapeutic strategy designed to overcome the limitations of T cell-based CAR therapies in solid tumors. However, CAR-T cells have shown limited efficacy in solid tumors due to poor tumor penetration and strong immunosuppressive signals in the tumor microenvironment (TME). CAR-M therapy has emerged as a promising alternative that may overcome these limitations. CAR-Ms are engineered macrophages that detect tumor antigens, enabling their accumulation in solid tumors where they destroy cancer cells by phagocytosis. Unlike CAR-T cells, CAR-Ms can remodel the TME and initiate innate and adaptive immune responses with lower risk of cytokine release syndrome (CRS). This review presents current approaches for engineering CAR-Ms and discusses how they engage tumor antigens within the TME. We also summarize recent advances in CAR-M delivery systems and functional design and highlight the status of clinical and preclinical studies evaluating CAR-M-based therapies. Despite remaining limitations, CAR-M therapy provides a compelling platform for solid tumor immunotherapy and is likely to play an expanding role in future cancer treatment.

Keywords:  CAR-M; Cancer immunotherapy; Macrophage; Macrophage engineering; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.intimp.2025.114720
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 30. pii: S0925-4439(25)00228-5. [Epub ahead of print] 167880

Angiogenesis and immune microenvironment in triple-negative breast cancer: Targeted therapy.

Ying Zhang, Hao Yang, Yanhong Jiang, Yijing Jiang, Renfang Mao.

  Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

Keywords:  Combination therapy strategies; Immune checkpoint inhibition; Targeted therapy; Triple-negative breast cancer; Tumor angiogenesis; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2025.167880
Biochim Biophys Acta Rev Cancer. 2025 Apr 29. pii: S0304-419X(25)00081-2. [Epub ahead of print] 189339

Research progress on the regulatory role of lactate and lactylation in tumor microenvironment.

Chunyan Gao, Jiali Li, Baoen Shan.

  The tumor microenvironment (TME) arises from the dynamic interactions between tumor cells and the surrounding medium, including a variety of cell types and extracellular components, which have an important impact on the genesis and development of tumors. A key player in TME is lactate, a metabolic byproduct of glycolysis, which serves as a significant energy source. Lactate has direct implications on the survival and differentiation of immune cells, the metabolic reprogramming and progression of tumor cells. Moreover, lactylation, a unique post-translational modification, exerts a regulatory effect on TME by affecting gene transcription via adding lactate groups to both histone and non-histone proteins. This review systematically and comprehensively synthesizes emerging evidence on how the lactate-lactylation axis drives immune evasion, therapy resistance, and TME remodeling, highlighting the therapeutic targets related to lactate and lactylation that dismantle this metabolic-epigenetic crosstalk.

Keywords:  Lactate; Lactylation; Metabolic regulation; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189339
Cell Biol Toxicol. 2025 Apr 26. 41(1): 75

Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy.

Chuhan Ma, Huixin Hu, Hao Liu, Chongli Zhong, Baokang Wu, Chao Lv, Yu Tian.

  The vulnerability of tumor cells to lipid peroxidation, driven by redox imbalance and lipid overabundance within the tumor microenvironment (TME), has become a focal point for novel antitumor strategies. Ferroptosis, a form of regulated cell death predicated on lipid peroxidation, is emerging as a promising approach. Beyond their role in directly eliminating tumor cells, lipid peroxidation and its products, such as 4-hydroxynonenal (HNE), exert an additional influence by damaging DNA and shaping an environment conducive to tumor growth and metastasis. This process polarizes macrophages towards a pro-inflammatory phenotype, dampens the antigen-presenting capacity of dendritic cells (DCs), and undermines the cytotoxic functions of T and NK cells. Furthermore, it transforms neutrophils into pro-tumorigenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). The lipid peroxidation of stroma cells also contributes to tumor progression. Although advanced nanotherapies have shown the ability to target tumor cells precisely, they often overlook the nuanced effects of lipid peroxidation products. In this review, we highlight a synergistic mechanism in which lipid peroxidation products and ferroptosis contribute to an immunosuppressive state that is temporally distinct from cell death. This insight broadens our understanding of ferroptosis-derived immunosuppression, encompassing all types of immune cells within the TME. This review aims to catalyze further research in this underexplored area, emphasizing the potential of lipid peroxidation products to hinder the clinical translation of ferroptosis-based therapies.

Keywords:  Active aldehyde; Ferroptosis; Immune cells; Lipid peroxidation; Oxidized lipid

DOI:  https://doi.org/10.1007/s10565-025-10025-7
J Exp Clin Cancer Res. 2025 Apr 25. 44(1): 131

Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.

Saber Imani, Reyhaneh Farghadani, Ghazaal Roozitalab, Mazaher Maghsoudloo, Mahdieh Emadi, Atefeh Moradi, Behnaz Abedi, Parham Jabbarzadeh Kaboli.

  This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

Keywords:  Breast cancer; Cancer vaccine; Cold tumor; Hot tumor; Immune checkpoint; Immunotherapy

DOI:  https://doi.org/10.1186/s13046-025-03394-8
J Cancer. 2025 ;16(7): 2261-2274

Nano-strategies for Targeting Tumor-Associated Macrophages in Cancer immunotherapy.

Qian Li, Jingwei Xu, Runjia Hua, Hanye Xu, Yongyou Wu, Xiaju Cheng.

  Tumor-associated macrophages (TAMs) are one type of the most abundant immune cells within tumor, resulting in immunosuppresive tumor microenvironment and tumor resistance to immunotherapy. Thus, targeting TAMs is a promising therapeutic strategy for boosting cancer immunotherapy. This study provides an overview of current therapeutic strategies targeting TAMs, which focus on blocking the recruitment of TAMs by tumors, regulating the polarization of TAMs, and directly eliminating TAMs using various nanodrugs, especially with a new categorization based on the specific signaling pathways, such as NF-κB, HIF-1α, ROS, STAT, JNK, PI3K, and Notch involved in their regulatory mechanism. The latest developments of nanodrugs modulating these pathways are discussed in determining the polarization of TAMs and their role in the tumor microenvironment. Despite the challenges in clinical translation and the complexity of nanodrug synthesis, the potential of nanodrugs in enhancing the effectiveness of cancer immunotherapy is worthy of expecting.

Keywords:  Cancer immunotherapy; M1 polarization; Nanodrugs; Signaling pathways; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/jca.108194
Pathol Res Pract. 2025 Apr 28. pii: S0344-0338(25)00184-0. [Epub ahead of print]270 155992

EZH2 regulatory roles in cancer immunity and immunotherapy.

Keywan Mortezaee.

  Enhancer of zeste homolog 2 (EZH2) is a polycomb repressor complex 2 (PRC2) subunit that is responsible for silencing expression of target genes through generation of lysine 27 trimethylation on histone H3 (H3K27Me3). EZH2 is an oncogene aberrantly expressed in human cancers, and its overexpression favors immune escape and metastasis. Immune escape occurs via the impact of EZH2 on hampering antigen expression machinery, stabilizing FOXP3 in regulatory T cells (Tregs), inhibiting recruitment and activity of natural killer (NK) and CD8+ T cells, and inducing recruitment and activity of myeloid-derived suppressor cells (MDSCs). Besides, EZH2 also promotes intra-tumoral recruitment of tumor-associated macrophages (TAMs). A point is that pharmacologic EZH2 inhibition (not knockdown) seemingly promotes polarization of macrophages toward pro-tumor M2 phenotype, which defines resistance mechanism. Besides, increased EZH2 expression after anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and a rise in the tumoral expression of programmed death-ligand 1 (PD-L1) after EZH2 inhibition account for secondary immunosuppression in tumor ecosystem after immunotherapy, indicating the applicability of using EZH2 targeted therapies as a combinatory approach with anti-programmed death-1 (PD-1) or anti-CTLA-4 therapy. Such combination reinvigorates anti-tumor immunity and presumably hampers T cell exhaustion and acting as a promising regimen for retarding cancer growth.

Keywords:  Cytotoxic T lymphocyte associated antigen-4 (CTLA-4); Enhancer of zeste homolog 2 (EZH2); Polycomb repressor complex 2 (PRC2); Programmed death-1 (PD-1); Regulatory T cell (Treg)

DOI:  https://doi.org/10.1016/j.prp.2025.155992
J Nanobiotechnology. 2025 Apr 26. 23(1): 319

Macrophage-derived exosomes in cancer: a double-edged sword with therapeutic potential.

Long Liu, Siying Zhang, Yuqing Ren, Ruizhi Wang, Yuyuan Zhang, Siyuan Weng, Zhaokai Zhou, Peng Luo, Quan Cheng, Hui Xu, Yuhao Ba, Anning Zuo, Shutong Liu, Zaoqu Liu, Xinwei Han.

  Solid cancer contains a complicated communication network between cancer cells and components in the tumor microenvironment (TME), significantly influencing the progression of cancer. Exosomes function as key carriers of signaling molecules in these communications, including the intricate signalings of tumor-associated macrophages (TAMs) on cancer cells and the TME. With their natural lipid bilayer structures and biological activity that relates to their original cell, exosomes have emerged as efficient carriers in studies on cancer therapy. Intrigued by the heterogeneity and plasticity of both macrophages and exosomes, we regard macrophage-derived exosomes in cancer as a double-edged sword. For instance, TAM-derived exosomes, educated by the TME, can promote resistance to cancer therapies, while macrophage-derived exosomes generated in vitro have shown favorable potential in cancer therapy. Here, we depict the reasons for the heterogeneity of TAM-derived exosomes, as well as the manifold roles of TAM-derived exosomes in cancer progression, metastasis, and resistance to cancer therapy. In particular, we emphasize the recent advancements of modified macrophage-derived exosomes in diverse cancer therapies, arguing that these modified exosomes are endowed with unique advantages by their macrophage origin. We outline the challenges in translating these scientific discoveries into clinical cancer therapy, aiming to provide patients with safe and effective treatments.

Keywords:  Cancer therapy; Exosomes; Macrophage-derived exosomes; Modified exosomes; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12951-025-03321-1
J Immunother Cancer. 2025 May 02. pii: e011609. [Epub ahead of print]13(5):

Targeting nerve growth factor: an Achilles' heel for tumors?

Elizabeth Repasky, Hemn Mohammadpour.

  A tumor's ability to attract innervation is a critical factor in tumor progression and immune escape, with the sympathetic nervous system playing a major role. Catecholamines released by sympathetic nerves activate adrenergic receptors on tumor cells, enhancing growth and resistance to therapies, while activation of adrenergic receptors on immune cells triggers immunosuppressive activity in the tumor microenvironment. Nerve growth factor (NGF) produced by tumor cells is a key driver of tumor innervation, making it a promising target for novel therapeutic strategies. In this commentary, we highlight a recent study by Yang et al, which examines NGF single-chain variable fragment (scFv)-secreting chimeric antigen receptor(CAR) T cells and the impact of NGF neutralization by CAR T cells on CAR T-cell function and the remodeling of the tumor microenvironment. This work shows that we may be able to exploit a tumor-derived survival factor as a vulnerability and a means to enhance antitumor immune activity.

Keywords:  Chimeric antigen receptor - CAR; Immunosuppression; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-011609
Discov Oncol. 2025 Apr 28. 16(1): 628

Serine metabolism in tumor progression and immunotherapy.

Dong Huang, Hui Cai, HaiYu Huang.

  Serine plays a vital role in various metabolic processes including the synthesis of proteins and other amino acids, which are essential for the cell proliferation and growth. Cancer cells either absorb exogenous serine or produce it through the serine synthesis pathway, enabling the generation of intracellular glycine and one-carbon units, which are crucial for nucleotide biosynthesis. This metabolic process, referred to as serine-glycine-one-carbon (SGOC) metabolism, is essential for tumorigenesis and exhibits considerable complexity and clinical significance. Enzymes involved in the SGOC pathway are linked to tumor growth, metastasis, and resistance to therapies. The SGOC pathway is a vital metabolic network that facilitates cell survival and proliferation, especially in aggressive cancers. Understanding how this network is regulated is crucial for tackling tumor heterogeneity and recurrence. This review emphasizes recent advancements in understanding the roles and effects of the SGOC metabolic pathway in the context of cancer progression. Additionally, it outlines the complex influences of the SGOC metabolic pathway on the tumor microenvironment (TME), offering potential strategies to enhance cancer immunotherapy.

Keywords:  Immunotherapy; One-carbon metabolism; Serine; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1007/s12672-025-02358-w
Cell Signal. 2025 Apr 25. pii: S0898-6568(25)00240-2. [Epub ahead of print]132 111827

CAF-mediated tumor vascularization: From mechanistic insights to targeted therapies.

Zhi Zhang, Qing Zhang, Yang Wang.

  Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.

Keywords:  Cancer-associated fibroblasts, Angiogenesis; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellsig.2025.111827
Front Oncol. 2025 ;15 1571583

The role and clinical significance of tumor-associated macrophages in the epithelial-mesenchymal transition of lung cancer.

Lei Liao, Ying-Xia Wang, Su-Su Fan, Ying-Yue Hu, Xue-Chang Wang, Xuan Zhang.

  Lung cancer remains the leading cause of cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) and epithelial-mesenchymal transition (EMT) are key drivers of lung cancer metastasis and drug resistance. M2-polarized TAMs dominate the immunosuppressive tumor microenvironment (TME) and promote EMT through cytokines such as TGF-β, IL-6, and CCL2. Conversely, EMT-transformed tumor cells reinforce TAM recruitment and M2 polarization through immunomodulatory factors such as CCL2 and ZEB1, thereby establishing a bidirectional interplay that fuels tumor progression. Current evidence on this interaction remains fragmented, and a comprehensive review of the TAM-EMT regulatory network and its therapeutic implications is lacking. This review systematically integrates the bidirectional regulatory mechanisms between TAMs and EMT, highlighting their roles in lung cancer progression. It also summarizes emerging therapeutic strategies targeting TAM polarization and the EMT process, emphasizing their potential for clinical translation. This study fills the gap in systematic reviews on the interaction between TAMs and EMT, providing a comprehensive theoretical foundation for future research and the development of novel lung cancer therapies.

Keywords:  epithelial-mesenchymal transformation; lung cancer; tumor microenvironment; tumor therapy; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fonc.2025.1571583
Mol Ther. 2025 Feb 05. pii: S1525-0016(24)00844-X. [Epub ahead of print]33(2): 723-733

Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor.

Wonkyung Oh, Alyssa Min Jung Kim, Deepika Dhawan, Deborah W Knapp, Seung-Oe Lim.

  Immune checkpoint blockade therapy targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has shown remarkable clinical impact in multiple cancer types. Nonetheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here, we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the monocarboxylate transporter 1 (MCT-1) inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade-resistant tumors. The findings of this study provide a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment to overcome the tumor resistance to PD-1/PD-L1 blockade therapy.

Keywords:  PD-L1; PD-l/PD-L1 blockade therapy; antibody; antibody-drug conjugate; immunotherapy; lactic acid; resistance; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ymthe.2024.12.044
Nat Immunol. 2025 May;26(5): 665-677

Cholinergic T cells revitalize the tumor immune microenvironment: TIME to ChAT.

Chunxing Zheng, Shaofeng Liu, Nastaran Fazel Modares, Michael St Paul, Tak W Mak.

Crosstalk between the nervous system and the immune system shapes the tumor microenvironment. Cholinergic T cells, a unique population of T cell antigen receptor-induced acetylcholine-producing T cells, have emerged as an integrative interface between these two fundamental body systems. Here we review the distinct characteristics and functions of cholinergic T cells in cancer settings. We first outline the expression of choline acetyltransferase and the cholinergic machinery in T cells. We then describe the dysfunctional state of choline acetyltransferase-expressing T cells in cancer and delve into their modulatory effects on T cells, cancer cells and the tumor microenvironment, including its populations of immune cells, its vasculature and its nerves. We also discuss the clinical implications of harnessing the potential of cholinergic T cells and future directions for increasing our understanding of their importance and possible exploitation.

DOI: https://doi.org/10.1038/s41590-025-02144-4
Exp Cell Res. 2025 Apr 29. pii: S0014-4827(25)00177-6. [Epub ahead of print] 114581

The Dynamic Interplay between Melanoma Cells and CAFs: Implications Drug Resistance and Immune Evasion and Possible Therapeutics.

Chou-Yi Hsu, Raed Obaid Saleh, Jaafaru Sani Mohammed, Nasrin Mansuri, Rekha M M, Mayank Kundlas, Alex Anand, Samir Sahoo, Ahmed Hussein Zwamel, Hanen Mahmod Hulail.

  Melanoma, a malignancy of varying prognoses across primary sites (cutaneous, ocular, and mucosal), typically displays peculiar treatment challenges in metastatic and refractory settings. Cancer-associated fibroblasts (CAFs) have long been recognized as pivotal components within melanoma's tumor microenvironment (TME), originating from various sources and manifesting considerable heterogeneity. These cells actively produce extracellular matrix (ECM), induce angiogenesis, provide metabolic support, contribute to drug resistance, and feed tumor progression and metastasis. Among the many growth factors and cytokines they secrete, including TGF-β and IL-6, they aid in anti-tumor immunity by recruiting immunosuppressive cells and inhibiting cytotoxic T-cell activity, contributing to immune evasion. These dynamic cells sculpt the tumor's niche, allowing cancer cells to survive and proliferate, and their existence is widely correlated with poor prognosis. Taking a cue from the previously established groundwork of how the surroundings heavily influence tumor development, this review attempts to profile the intricate interaction of melanoma cells with the CAFs, the ECM, and signaling molecules. We explore different subtypes of CAFs, their origins, and how they have evolved in their pro-tumorigenic roles in melanoma. Additionally, we review recent advancements in the therapeutic arsenal targeting CAFs to achieve a more effective treatment response. By detailing the specific roles played by different CAFs subtypes in the modulation of immuno-responses and treatment outcomes, this review will further provide insights into the targeted therapy to disrupt CAFs-mediated tumor support in melanoma.

Keywords:  Cancer-Associated Fibroblasts; Extracellular Matrix; Melanoma; Metastasis; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.yexcr.2025.114581
Nihon Yakurigaku Zasshi. 2025 ;160(3): 158-162

[Regulation of myeloid-derived suppressor cells by glutamate].

Masashi Tachibana.

Myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity in tumor bearers, which leads to tumor progression. Immune checkpoint blockers (ICBs) demonstrated significant efficiency against various cancers; however, their success rate is limited to approximately 20-30% in patients with cancer. To address this limitation, predictive biomarkers and combination therapies are required. Since MDSCs are supposed to be crucial for the resistance to ICBs, targeting MDSCs could be a promising approach for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF), widely used as prophylaxis and therapy for febrile neutropenia (FN), has been shown to significantly reduce its incidence. However, G-CSF has been reported to promote tumor progression caused by the enhancing the proliferation of MDSCs. We found that G-CSF enhances the immunosuppressive activity of MDSCs through the upregulation of γ-glutamyltransferase 1 (GGT1). GGT1, an enzyme hydrolyzing extracellular glutathione, is reported to be a marker for early-stage cancers and promote tumor progression. It is suggested that GGT1 increases glutamate levels through glutathione hydrolysis and that metabotropic glutamate receptor signaling enhances the immunosuppressive activity of MDSCs. Moreover, in FN mouse models, we observed that G-CSF promoted tumor progression, while the inhibition of GGT abolished. Together, the inhibition of GGT can mitigate the tumor-promoting effects of MDSCs without compromising the beneficial effect of G-CSF. These insights should lead to the safer and more effective cancer immunotherapy.

DOI: https://doi.org/10.1254/fpj.25009
Int J Biol Sci. 2025 ;21(6): 2606-2628

Unraveling the breast cancer tumor microenvironment: crucial factors influencing natural killer cell function and therapeutic strategies.

Feifei Li, Chunfang Gao, Yan Huang, Yu Qiao, Hongxiao Xu, Sheng Liu, Huangan Wu.

  Natural killer (NK) cells have emerged as a novel and effective treatment for breast cancer. Nevertheless, the breast cancer tumor microenvironment (TME) manifests multiple immunosuppressive mechanisms, impeding the proper execution of NK cell functions. This review summarizes recent research on the influence of the TME on the functionality of NK cells in breast cancer. It delves into the effects of the internal environment of the TME on NK cells and elucidates the roles of diverse stromal components, immune cells, and signaling molecules in regulating NK cell activity within the TME. It also summarizes therapeutic strategies based on small-molecule inhibitors, antibody therapies, and natural products, as well as the progress of research in preclinical and clinical trials. By enhancing our understanding of the immunosuppressive TME and formulating strategies to counteract its effects, we could fully harness the therapeutic promise of NK cells in breast cancer treatment.

Keywords:  breast cancer tumor microenvironment; immunosuppressive mechanisms; intrinsic metabolic factors; natural killer cells; stromal components; therapeutic strategies

DOI:  https://doi.org/10.7150/ijbs.108803
bioRxiv. 2025 Apr 13. pii: 2025.02.07.632847. [Epub ahead of print]

Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.

Yifei Guo, Jennifer M Finan, Alexandra Q Bartlett, Shamilene Sivagnanam, Katie E Blise, Nell Kirchberger, Konjit Betre, Grace A McCarthy, Kevin Hawthorne, Canping Chen, Aaron Grossberg, Zheng Xia, Lisa M Coussens, Rosalie C Sears, Jonathan R Brody, Robert Eil.

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth due to a novel role of HuR inducing T-cell suppression. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states and diminished myeloid phenotypes by comprehensive spatial profiling of the PDAC TME. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Translating these findings, we demonstrated that HuR depletion sensitized PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. For the first time, we show that HuR facilitates tumor immune suppression in PDAC by inhibiting T cell infiltration and function and implicate targeting HuR as a potential therapeutic strategy in combination with immunotherapy.

DOI: https://doi.org/10.1101/2025.02.07.632847
Cancers (Basel). 2025 Apr 21. pii: 1379. [Epub ahead of print]17(8):

Single-Cell Profiling Reveals Global Immune Responses During the Progression of Murine Epidermal Neoplasms.

Xiying Fan, Tonya M Brunetti, Kelsey Jackson, Dennis R Roop.

   BACKGROUND/OBJECTIVES: Immune cells determine the role of the tumor microenvironment during tumor progression, either suppressing tumor formation or promoting tumorigenesis. This study aimed to fully characterize immune cell responses during skin tumor progression.
METHODS: Using single-cell RNA sequencing, we analyzed the profile of immune cells in the tumor microenvironment of control mouse skins and skin tumors at the single-cell level.
RESULTS: We identified 15 CD45+ immune cell clusters, which broadly represent the most functionally characterized immune cell types including macrophages, Langerhans cells (LC), conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), migratory/mature dendritic cells (mDC), dendritic epidermal T cells (DETC), dermal γδ T cells (γδT), T cells, regulatory T cells (Tregs), natural killer cells (NK), type 2 innate lymphoid cells (ILC2), neutrophils (Neu), mast cells (Mast), and two proliferating populations (Prolif.1 and Prolif.2). Skin tumor progression reprogramed immune cells and led to a marked increase in the relative percentages of macrophages, cDC2, mDC, Tregs, and Neu. Macrophages, the largest cell cluster of immune cells in skin tumors. In addition, macrophages emerged as the predominant communication 'hub' in skin tumors, highlighting the importance of macrophages during skin tumor progression. In contrast, other immune cell clusters decreased during skin tumor progression, including DETC, γδT, ILC2, and LC. In addition, skin tumor progression dramatically upregulated Jak2/Stat3 expression and the interferon response across various immune cell clusters. Further, skin tumor progression activated T cells and NK cells indicated by elevated expression of IFN-γ and Granzyme B in skin tumors. Meanwhile, a pronounced infiltration of M2-macrophages and Tregs in skin tumors created an immunosuppressive microenvironment, consistent with the elevated expression of the Stat3 pathway in skin tumors.
CONCLUSIONS: Our study elucidates the immune cell landscape of epidermal neoplasms, offering a comprehensive understanding of the immune response during skin tumor progression and providing new insights into cancer immune evasion mechanisms.

Keywords:  immune response; scRNA-seq; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17081379
Cancer Treat Rev. 2025 Apr 23. pii: S0305-7372(25)00065-9. [Epub ahead of print]137 102943

Chimeric antigen receptor NK cells for breast cancer immunotherapy.

Nisha Wu, Ning Yang, Shiqi Zhang, Haoran Wu, Xuechun Fang, Wanying Lin, Yi Zhang, Xiaowei Qi, Ying Gong.

  Breast cancer, a predominant malignancy afflicting women globally, demands innovative therapeutic strategies beyond traditional treatments such as surgery, chemotherapy, radiotherapy, and endocrine therapy. Among the emerging therapies, immunotherapy has demonstrated substantial promise, particularly employing chimeric antigen receptor (CAR) technology. This review elucidates the prospect of CAR-modified natural killer (NK) cells in treating breast cancer. NK cells, vital components of the immune system, possess the capability to non-specifically target and extinguish neoplastic cells. Through genetic engineering, CAR constructs targeting specific breast cancer antigens, including HER2, EGFR, PD-L1, MSLN, and Trop2, are integrated into NK cells, thereby enhancing their tumor recognition and cytotoxicity. The review delves into the structural optimization of CAR-NK cells, discussing design elements such as scFv, hinge regions, and activation signals, and emphasizes strategies to augment CAR-NK cell functionality and persistence within the tumor microenvironment. Combining CAR-NK cells with other therapeutic modalities (such as chemotherapy and checkpoint inhibitors) is explored to enhance therapeutic efficacy. Preclinical researches emphasized the efficacy of CAR-NK cells in targeting breast cancer cells, paving the way for future clinical applications and offering hope for improved outcomes in breast cancer patients.

Keywords:  Breast cancer; Chimeric antigen receptor; Clinical trials; Immunotherapy; Natural killer cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctrv.2025.102943
Cancers (Basel). 2025 Apr 11. pii: 1298. [Epub ahead of print]17(8):

Role of Neutrophils in Anti-Tumor Activity: Characteristics and Mechanisms of Action.

Xin Chen, Bingdi Chen, Huadong Zhao.

  As one of the leading components in the immune system, neutrophils in the tumor microenvironment (TME) have received considerable attention in recent years. The tumor-killing effects of neutrophils in a variety of tumors have been reported. However, the functions of neutrophils in tumors remain to be completely elucidated, and both anti-tumor and tumor-promotion activities have been reported. This review focuses on the characteristics of neutrophils and their mechanisms of action in the TME, with an emphasis on their anti-tumor activity, including reactive oxygen species (ROS)-induced tumor killing, cytotoxic T lymphocytes (CTLs)-induced tumor killing, trogocytosis, cytotoxic enzymes, and trained immunity. Furthermore, the possible targets and methods of tumor treatment regimens for neutrophils are explored, with the aim of exploring the use of neutrophils in the future as a potential anti-tumor treatment strategy.

Keywords:  anti-tumor activity; cytotoxic T lymphocytes; neutrophils; phenotypes of neutrophils; trained immunity; trogocytosis

DOI:  https://doi.org/10.3390/cancers17081298
Lab Chip. 2025 Apr 28.

Vascularized tumor-on-a-chip to investigate immunosuppression of CAR-T cells.

Rajul S Bains, Tara G Raju, Layla C Semaan, Anton Block, Yukiko Yamaguchi, Saul J Priceman, Steven C George, Venktesh S Shirure.

Chimeric antigen receptor (CAR)-T cell immunotherapy, effective in blood cancers, shows limited success in solid tumors, such as prostate, pancreatic, and brain cancers due, in part, to an immunosuppressive tumor microenvironment (TME). Immunosuppression affects various cell types, including tumor cells, macrophages, and endothelial cells. Conventional murine-based models offer limited concordance with human immunology and cancer biology. Therefore, we have developed a human "tumor-on-a-chip" (TOC) platform to model elements of immunosuppression at high spatiotemporal resolution. Our TOC features an endothelial cell-lined channel that mimics features of an in vivo capillary, such as cell attachment and extravasation across the endothelium and into the TME. Using 70 kDa dextran and fluorescence-recovery-after-photobleaching (FRAP), we confirmed physiologic interstitial flow velocities (0.1-1 μm s-1). Our device demonstrates that tumor-derived factors can diffuse in the opposite direction of interstitial flow to reach the endothelium up to 200 μm away, and at concentrations as high as 20% of those at the tumor margin. M2-like immunosuppressive macrophages and endothelial cells affect prostate tumor cell growth, clustering, and migration. M2-like macrophages also induce PD-L1 and inhibit ICAM-1 gene expression on the adjacent endothelium in a pattern that limits CAR-T cell extravasation and effector function. This observation is abrogated in the presence of the anti-PD-L1 drug atezolizumab. These results provide mechanistic insight for in vivo observations showing limited CAR-T cell extravasation and effector function in solid tumors. Furthermore, they point to a specific role of M2 macrophages in driving CAR-T cell migration into and within the TME and could prove useful in the development of novel therapies to improve solid tumor CAR-T cell therapies.

DOI: https://doi.org/10.1039/d4lc01089b
Explor Target Antitumor Ther. 2025 ;6 1002312

Cytokine-based immunotherapy for gastric cancer: targeting inflammation for tumor control.

Mathan Muthu Chinakannu Marimuthu, Bhavani Sowndharya Balamurugan, Vickram Agaram Sundaram, Saravanan Anbalagan, Hitesh Chopra.

  Emerging cancer immunotherapy methods, notably cytokine-based ones that modify immune systems' inflammatory reactions to tumor cells, may help slow gastric cancer progression. Cytokines, tiny signaling proteins that communicate between immune cells, may help or hinder cancer growth. Pro-inflammatory cytokines encourage tumor development, whereas antitumor ones help the host reject cancer cells. This study considers cytokine-targeted methods for gastric cancer pro-inflammatory and antitumor immune responses. Researchers want to renew immune cells like cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells by delivering cytokines like interleukin-2 (IL-2), interferons (IFNs), and tumor necrosis factor-alpha (TNF-α) to activate inflammatory pathways and combat tumors. Since cytokines have significant pleiotropic effects, their therapeutic use is difficult and may cause excessive systemic inflammation or immunological suppression. This review covers current advancements in synthetic cytokines, cytokine-conjugates, and local administration of these aimed to enhance the therapeutic index: increase the potential to kill cancer cells while minimizing off-target damage. The study examines the relationship between cytokines and tumor microenvironment (TME), revealing the role of immunosuppressive cytokines like IL-10 and transforming growth factor-beta (TGF-β) in promoting an immune-evasive phenotype. These results suggest that inhibitory pathway targeting, and cytokine-based therapy may overcome resistance mechanisms. Cytokine-based immunotherapies combined with immune checkpoint inhibitors are predicted to change gastric cancer therapy and rebuild tumor-immune microenvironment dynamics, restoring antitumor immunity. Comprehensive data from current clinical studies will assist in establishing the position of these treatments in gastric cancer.

Keywords:  Cytokine-based immunotherapy; gastric cancer; inflammation; interferons (IFNs); interleukin-2 (IL-2); tumor microenvironment (TME); tumor necrosis factor-alpha (TNF-α)

DOI:  https://doi.org/10.37349/etat.2025.1002312
Int Immunopharmacol. 2025 Apr 27. pii: S1567-5769(25)00715-5. [Epub ahead of print]156 114725

Dual cytokine-engineered macrophages rejuvenate the tumor microenvironment and enhance anti-PD-1 therapy in renal cell carcinoma.

Xin Liu, Ranran Jiang, Yujun Xu, Xiaodi Xu, Lin Fang, Ge Gao, Lulu Han, Yuxin Chen, Hongwei Du, Ying Cai, Fei Zhu, Mingjing Chen, Kaidi Wang, Hailong Li, Gang Wang, Changyi Quan.

  Despite advances in PD-1 blockade therapy, the immunosuppressive tumor microenvironment (TME) limits its efficacy in renal cell carcinoma (RCC). Here, we developed dual-cytokine-engineered macrophages co-delivering IL-12 and CXCL-9 to reprogram TME and enhance anti-PD-1 responsiveness. Single-cell RNA sequencing revealed that RCC harbor abundant M2-like tumor-associated macrophages (TAMs), which correlate with T-cell exhaustion. In vitro, engineered macrophages polarized M2-like TAMs to antitumor M1 phenotypes, secreted CXCL-9 to recruit cytotoxic T cells, and released IL-12 to amplify T/NK cell activation. In vivo, intravenously administered engineered macrophages homed to tumors, reshaped the TME by increasing CD8+ T cells, dendritic cells, and NK cells while reducing immunosuppressive Tregs and MDSCs. This approach synergized with PD-1 blockade, resulting in a 2.5-fold greater tumor growth inhibition compared to anti-PD-1 monotherapy. This dual-cytokine macrophage platform offers a novel strategy to overcome resistance to checkpoint inhibitors in RCC by delivering cytokine and remodeling TME, with implications for clinical translation.

Keywords:  Macrophage; PD-1 inhibitor; Renal cell carcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2025.114725