近日，中国科学院分子细胞卓越创新中心许琛琦等研究人员合作发现，耗竭相关的胆固醇缺乏抑制抗肿瘤免疫的细胞毒性臂。2023年5月26日，《癌细胞》杂志在线发表了这项成果。

研究人员分析了肿瘤微环境中的胆固醇图谱，发现瘤内T细胞有胆固醇缺乏，而免疫抑制性骨髓细胞和肿瘤细胞则显示有大量的胆固醇。低胆固醇水平抑制了T细胞的增殖，并导致自噬介导的细胞凋亡，特别是对细胞毒性T细胞。在肿瘤微环境中，氧化甾醇介导LXR和SREBP2途径的相互改变，导致T细胞的胆固醇缺乏，随后导致异常的代谢和信号途径，推动T细胞耗竭/功能障碍。嵌合抗原受体T（CAR-T）细胞中LXRβ的去除导致对实体瘤的抗肿瘤功能改善。由于T细胞的胆固醇代谢和氧化甾醇一般与其他疾病有关，新的机制和胆固醇正常化策略可能在其他地方有潜在的应用。

据了解，靶向胆固醇代谢治疗癌症的概念已经在临床上得到了广泛的测试，但收益不大，这就要求人们对瘤内细胞的胆固醇代谢有一个完整的了解。

附：英文原文

Title: Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity

Author: Chengsong Yan, Lin Zheng, Shutan Jiang, Haochen Yang, Jun Guo, Lu-yi Jiang, Tongzhou Li, Haosong Zhang, Yibing Bai, Yu Lou, Qi Zhang, Tingbo Liang, Wolfgang Schamel, Haopeng Wang, Weiwei Yang, Guangchuan Wang, Zheng-jiang Zhu, Bao-Liang Song, Chenqi Xu

Issue&Volume: 2023-05-26

Abstract: The concept of targeting cholesterol metabolism to treat cancer has been widely testedin clinics, but the benefits are modest, calling for a complete understanding of cholesterolmetabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironmentand find that intratumoral T cells have cholesterol deficiency, while immunosuppressivemyeloid cells and tumor cells display cholesterol abundance. Low cholesterol levelsinhibit T cell proliferation and cause autophagy-mediated apoptosis, particularlyfor cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocalalterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells,subsequently leading to aberrant metabolic and signaling pathways that drive T cellexhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cellsleads to improved antitumor function against solid tumors. Since T cell cholesterolmetabolism and oxysterols are generally linked to other diseases, the new mechanismand cholesterol-normalization strategy might have potential applications elsewhere.

DOI: 10.1016/j.ccell.2023.04.016

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00142-3