VSIG4 Promotes Tumour-Associated Macrophage M2 Polarization and Immune Escape in Colorectal Cancer via Fatty Acid Oxidation Pathway

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-22 DOI:10.1002/ctm2.70340

Jiafeng Liu, WenXin Zhang, Lu Chen, Xinhai Wang, Xiang Mao, Zimei Wu, Huanying Shi, Huijie Qi, Li Chen, Yuxin Huang, Jiyifan Li, Mingkang Zhong, Xiaojin Shi, Qunyi Li, Tianxiao Wang

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引用次数: 0

Abstract

Background

V-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC).

Methods

THP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs).

Results

CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages.

Conclusions

Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC.

Key points

Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis.
VSIG4 promotes fatty acid oxidation of macrophages and drives its M2-type polarization.
These VSIG4-expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment.
Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti-PD-1 antibody.

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VSIG4通过脂肪酸氧化途径促进结直肠癌肿瘤相关巨噬细胞M2极化和免疫逃逸

V-set and immunoglobulin domain containing 4 （VSIG4）是一种几乎只在巨噬细胞上表达的b7家族相关蛋白。其表达的差异介导了巨噬细胞极化状态的动态转变，但其潜在机制尚不清楚。我们试图揭示VSIG4与结直肠癌（CRC）中肿瘤相关巨噬细胞（tam）极化和肿瘤细胞免疫逃逸之间的相关性。方法采用表达不同水平VSIG4的THP-1单核细胞源性巨噬细胞进行体外研究。此外，利用共培养系统验证肿瘤细胞对巨噬细胞中VSIG4表达的影响，以及VSIG4表达水平对肿瘤细胞的影响。皮下异种移植模型评估了VSIG4阻断剂作为单一疗法和联合免疫检查点抑制剂（ICIs）的肿瘤生长抑制效果。结果结直肠癌细胞分泌乳酸促进巨噬细胞VSIG4的表达。相反，VSIG4通过促进M2巨噬细胞分泌肝素结合表皮生长因子，促进巨噬细胞M2极化，诱导肿瘤细胞恶性进展。体内实验证实，敲低VSIG4可抑制肿瘤生长，提高ICIs治疗效果。机制上，CRC细胞分泌的乳酸通过影响巨噬细胞VSIG4的表观遗传修饰促进其表达。此外，VSIG4通过激活JAK2/STAT3通路，增强巨噬细胞的脂肪酸氧化（FAO），上调PPAR-γ表达，最终诱导巨噬细胞M2极化。下调VSIG4或阻断FAO可逆转巨噬细胞的M2极化过程。结论本研究为VSIG4通过调控FAO重编程影响TAMs极化提供了分子基础，提示在巨噬细胞中靶向VSIG4可提高ICIs的疗效，为CRC免疫治疗提供了一种新的联合治疗策略。结直肠癌细胞通过H3K18la-METTL14-m6A轴分泌乳酸上调巨噬细胞VSIG4。VSIG4促进巨噬细胞脂肪酸氧化，驱动其m2型极化。这些表达vsig4的M2巨噬细胞促进肿瘤进展和免疫抑制微环境。抑制VSIG4表达可协同增强抗pd -1抗体的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.