Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
Cell Chem Biol. 2023 Sep 21;30(9):1076-1089.e11. doi: 10.1016/j.chembiol.2023.05.003. Epub 2023 May 25.
Lack of MHC-II is emerging as a causal factor in cancer immune evasion, and the development of small-molecule MHC-II inducers is an unmet clinical need. Here, we identified three MHC-II inducers, including pristane and its two superior derivatives, that potently induce MHC-II expression in breast cancer cells and effectively inhibit the development of breast cancer. Our data suggest that MHC-II is central in promoting the immune detection of cancer to increase the tumor infiltration of T cells and enhance anti-cancer immunity. By discovering the malonyl/acetyltransferase (MAT) domain in fatty acid synthase (FASN) as the direct binding target of MHC-II inducers, we demonstrate that evasion of immune detection and cancer metabolic reprogramming are directly linked by fatty acid-mediated MHC-II silencing. Collectively, we identified three MHC-II inducers and illustrated that lack of MHC-II caused by hyper-activated fatty acid synthesis to limit immune detection is a potentially widespread mechanism underlying the development of cancer.
MHC-II 的缺乏正在成为癌症免疫逃逸的一个因果因素，因此开发小分子 MHC-II 诱导剂是未满足的临床需求。在这里，我们鉴定了三种 MHC-II 诱导剂，包括 pristane 及其两种优越的衍生物，它们能够在乳腺癌细胞中强烈诱导 MHC-II 表达，并有效抑制乳腺癌的发展。我们的数据表明，MHC-II 是促进癌症免疫检测的核心，以增加 T 细胞浸润肿瘤，并增强抗肿瘤免疫。通过发现脂肪酸合酶 (FASN) 中的丙二酰/乙酰基转移酶 (MAT) 结构域是 MHC-II 诱导剂的直接结合靶标，我们证明了免疫检测的逃逸和癌症代谢重编程通过脂肪酸介导的 MHC-II 沉默直接相关。总的来说，我们鉴定了三种 MHC-II 诱导剂，并表明由过度激活的脂肪酸合成引起的 MHC-II 缺乏限制了免疫检测，这是癌症发展的一个潜在的广泛机制。
