Liu Jiafeng, Zhang WenXin, Chen Lu, Wang Xinhai, Mao Xiang, Wu Zimei, Shi Huanying, Qi Huijie, Chen Li, Huang Yuxin, Li Jiyifan, Zhong Mingkang, Shi Xiaojin, Li Qunyi, Wang Tianxiao
Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Clin Transl Med. 2025 May;15(5):e70340. doi: 10.1002/ctm2.70340.
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).
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).
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.
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.
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.
含V结构域和免疫球蛋白结构域4（VSIG4）是一种几乎仅在巨噬细胞上表达的B7家族相关蛋白。其表达差异介导巨噬细胞极化状态的动态转变，但其潜在机制仍不清楚。我们试图揭示VSIG4与结直肠癌（CRC）中肿瘤相关巨噬细胞（TAM）极化及肿瘤细胞免疫逃逸之间的相关性。
使用表达不同水平VSIG4的THP-1单核细胞衍生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阻断作为单一疗法以及与免疫检查点抑制剂（ICI）联合使用时的肿瘤生长抑制疗效。
CRC细胞分泌乳酸以促进巨噬细胞中VSIG4的表达。相反，VSIG4促进巨噬细胞M2极化，并通过促进M2巨噬细胞分泌肝素结合表皮生长因子诱导肿瘤细胞的恶性进展。体内实验证实，敲低VSIG4可抑制肿瘤生长并提高ICI治疗的疗效。机制上，CRC细胞分泌的乳酸通过影响巨噬细胞中VSIG4的表观遗传修饰来促进其表达。此外，VSIG4增强巨噬细胞的脂肪酸氧化（FAO），并通过激活JAK2/STAT3途径上调PPAR-γ表达，最终诱导巨噬细胞的M2极化。VSIG4的下调或FAO的阻断可逆转巨噬细胞的M2极化过程。
我们的研究结果为VSIG4通过调节FAO重编程影响TAM极化提供了分子基础，表明靶向巨噬细胞中的VSIG4可增强ICI疗效，并代表了一种新的CRC免疫治疗联合治疗策略。
结直肠癌细胞通过H3K18la-METTL14-m6A轴分泌乳酸以上调巨噬细胞中的VSIG4。VSIG4促进巨噬细胞的脂肪酸氧化并驱动其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。
