Wei Huan, Niu Congyi, Shi Yue, Fang Yingfei, Yang Chengheng, Liu Jian, Xu Zhenjie
School of Basic Medical Science, Fudan University, Shanghai, China.
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Nat Commun. 2025 Jul 31;16(1):7035. doi: 10.1038/s41467-025-62134-w.
Immune checkpoint blockade (ICB) therapies for solid tumors often fail due to resistance, necessitating new strategies. While efforts target IFNγ signaling or antigen presentation, other immune evasion mechanisms are unclear. Here, we identify Monoacylglycerol O-Acyltransferase 1 (Mogat1) as a critical modulator of tumor immune evasion using an in vivo transcriptomic screen in progressing tumors. We find that tumors exploit Mogat1 to sequester fatty acids into triglycerides, a metabolic adaptation that fuels growth and fosters an immunosuppressive microenvironment, enabling immune escape. Genetic inhibition of Mogat1 suppresses tumor growth by promoting T-cell infiltration and enhancing their tumor-killing ability. Importantly, Mogat1 loss sensitizes tumors to PD-1 blockade, overcoming resistance and suggesting reduced reliance on conventional antigen presentation. Our findings reveal a lipid metabolism-centered immune evasion mechanism and highlight Mogat1 as a potential target to improve cancer immunotherapy.
实体瘤的免疫检查点阻断（ICB）疗法常常因耐药性而失败，因此需要新的策略。尽管人们致力于靶向干扰素γ信号传导或抗原呈递，但其他免疫逃逸机制尚不清楚。在这里，我们通过对进展期肿瘤进行体内转录组筛选，确定单酰甘油O-酰基转移酶1（Mogat1）是肿瘤免疫逃逸的关键调节因子。我们发现肿瘤利用Mogat1将脂肪酸隔离成甘油三酯，这是一种代谢适应，为肿瘤生长提供能量并促进免疫抑制微环境的形成，从而实现免疫逃逸。对Mogat1的基因抑制通过促进T细胞浸润并增强其肿瘤杀伤能力来抑制肿瘤生长。重要的是，Mogat1缺失使肿瘤对PD-1阻断敏感，克服了耐药性，并表明对传统抗原呈递的依赖性降低。我们的研究结果揭示了一种以脂质代谢为中心的免疫逃逸机制，并突出了Mogat1作为改善癌症免疫治疗的潜在靶点。
