肿瘤细胞治疗研究
英文原题：HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack.
细胞毒性淋巴细胞利用穿孔素在肿瘤细胞的质膜（PM）上形成孔道，从而使颗粒酶介导的细胞死亡得以发生。
细胞毒性淋巴细胞利用穿孔素在肿瘤细胞质膜（PM）上形成孔道，从而使颗粒酶进入并介导细胞死亡。然而，肿瘤代谢是否以及如何促进PM修复以逃避免疫，尚不清楚。本研究对111种代谢酶进行功能筛选，发现羟甲基戊二酰辅酶A合酶1（HMGCS1）是修复穿孔素诱导PM损伤的关键因子。HMGCS1通过启动胆固醇从头合成促进PM修复，增强肿瘤细胞对淋巴细胞介导杀伤的抵抗，并降低NK细胞、CAR-T和抗PD-1免疫疗法的疗效。除结构作用外，胆固醇还可直接结合带电多泡体蛋白4b（CHMP4B），增强其在PM的定位，从而促进PM修复。此外，致癌信号激活、细胞因子和缺氧均可诱导c-Jun活化，上调HMGCS1表达。在肺癌患者中，c-Jun活化、HMGCS1表达、胆固醇含量及PM上的CHMP4B升高均与抗PD-1免疫疗效降低相关。我们的发现揭示一种肿瘤免疫逃逸机制：HMGCS1通过激活胆固醇合成驱动胆固醇依赖性PM修复。靶向HMGCS1可增强免疫疗法效果。
Cytotoxic lymphocytes use perforin to form plasma membrane (PM) pores in tumor cells, thereby enabling granzyme-mediated cell death. However, whether and how tumor metabolism enables PM repair to evade immunity is unclear. In this study, using a functional screen targeting 111 metabolic enzymes, we identified hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) as critical for repairing perforin-induced PM damage. HMGCS1 promotes PM repair by initiating de novo cholesterol synthesis, enhancing tumor cell resistance to lymphocyte-mediated killing and impairing the efficacy of NK, CAR-T, and anti-PD-1-based immunotherapies. Beyond its structural role, cholesterol directly binds charged multivesicular body protein 4b (CHMP4B) to enhance its PM localization, facilitating PM repair. Furthermore, oncogenic activation, cytokine, and hypoxia induce c-Jun activation, up-regulating HMGCS1 expression. In lung cancer patients, elevated c-Jun activation, HMGCS1 expression, cholesterol content and PM CHMP4B correlate with reduced anti-PD-1 immunotherapy efficacy. Our findings reveal a tumor immune evasion mechanism wherein HMGCS1 drives cholesterol-dependent PM repair by activating the cholesterol synthesis. Targeting HMGCS1 enhances the effectiveness of immunotherapies.
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