Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Cancer Cell. 2023 Jul 10;41(7):1276-1293.e11. doi: 10.1016/j.ccell.2023.04.016. Epub 2023 May 26.
The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.
靶向胆固醇代谢治疗癌症的概念在临床上已经得到了广泛的检验，但疗效甚微，这就要求我们对肿瘤内细胞的胆固醇代谢有一个全面的了解。我们分析了肿瘤微环境中的胆固醇图谱，发现肿瘤内的 T 细胞存在胆固醇缺乏，而免疫抑制性的髓系细胞和肿瘤细胞则显示出胆固醇的丰富。低胆固醇水平抑制 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，氧化固醇通过调节 LXR 和 SREBP2 通路的相互作用导致 T 细胞的胆固醇缺乏，进而导致异常的代谢和信号通路，驱动 T 细胞耗竭/功能障碍。嵌合抗原受体 T（CAR-T）细胞中 LXRβ 的耗竭导致其对实体瘤的抗肿瘤功能得到改善。由于 T 细胞胆固醇代谢和氧化固醇通常与其他疾病有关，因此这种新的机制和胆固醇正常化策略可能在其他方面具有应用潜力。
