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Small-molecule MHC-II inducers promote immune detection and anti-cancer immunity via editing cancer metabolism
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2023-05-25 , DOI: 10.1016/j.chembiol.2023.05.003 Ling Huang 1 , Jun Zhang 1 , Bo Wei 1 , Shuangyang Chen 2 , Sitong Zhu 3 , Weiguan Qi 2 , Xiaoying Pei 1 , Lulu Li 1 , Weiguang Liu 1 , Yuzhi Wang 4 , Xiaojun Xu 3 , Lan-Gui Xie 2 , Liming Chen 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2023-05-25 , DOI: 10.1016/j.chembiol.2023.05.003 Ling Huang 1 , Jun Zhang 1 , Bo Wei 1 , Shuangyang Chen 2 , Sitong Zhu 3 , Weiguan Qi 2 , Xiaoying Pei 1 , Lulu Li 1 , Weiguang Liu 1 , Yuzhi Wang 4 , Xiaojun Xu 3 , Lan-Gui Xie 2 , Liming Chen 1
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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.
中文翻译：
小分子 MHC-II 诱导剂通过编辑癌症代谢促进免疫检测和抗癌免疫
MHC-II 的缺乏正在成为癌症免疫逃避的一个致病因素，而小分子 MHC-II 诱导剂的开发是一个未满足的临床需求。在这里，我们鉴定了三种MHC-II诱导剂，包括降植烷及其两种优质衍生物，它们能够有效诱导乳腺癌细胞中MHC-II的表达，并有效抑制乳腺癌的发展。我们的数据表明，MHC-II 在促进癌症的免疫检测、增加 T 细胞的肿瘤浸润并增强抗癌免疫力方面发挥着核心作用。通过发现脂肪酸合酶 (FASN) 中的丙二酰/乙酰转移酶 (MAT) 结构域作为 MHC-II 诱导剂的直接结合靶标，我们证明逃避免疫检测和癌症代谢重编程与脂肪酸介导的 MHC-II 直接相关沉默。总的来说，我们鉴定了三种 MHC-II 诱导剂，并说明由过度活化的脂肪酸合成导致的 MHC-II 缺乏限制了免疫检测，这是癌症发展的潜在广泛机制。
更新日期：2023-05-25
中文翻译：
小分子 MHC-II 诱导剂通过编辑癌症代谢促进免疫检测和抗癌免疫
MHC-II 的缺乏正在成为癌症免疫逃避的一个致病因素，而小分子 MHC-II 诱导剂的开发是一个未满足的临床需求。在这里，我们鉴定了三种MHC-II诱导剂，包括降植烷及其两种优质衍生物，它们能够有效诱导乳腺癌细胞中MHC-II的表达，并有效抑制乳腺癌的发展。我们的数据表明，MHC-II 在促进癌症的免疫检测、增加 T 细胞的肿瘤浸润并增强抗癌免疫力方面发挥着核心作用。通过发现脂肪酸合酶 (FASN) 中的丙二酰/乙酰转移酶 (MAT) 结构域作为 MHC-II 诱导剂的直接结合靶标，我们证明逃避免疫检测和癌症代谢重编程与脂肪酸介导的 MHC-II 直接相关沉默。总的来说，我们鉴定了三种 MHC-II 诱导剂，并说明由过度活化的脂肪酸合成导致的 MHC-II 缺乏限制了免疫检测，这是癌症发展的潜在广泛机制。
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