Small-molecule MHC-II inducers promote immune detection and anti-cancer immunity via editing cancer metabolism.
Small-molecule MHC-II inducers promote immune detection and anti-cancer immunity via editing cancer metabolism.
复制标题
DOI：
10.1016/j.chembiol.2023.05.003
复制
发表时间：
2023-05
影响因子：
8.6
通讯作者：
Ling Huang;Jun Zhang;Bo Wei;Shuangyang Chen;Si-jun Zhu;Weiguan Qi;Xiaoying Pei;Lulu Li;Weiguang Liu;Yuzhi Wang;Xiaojun Xu;Lan-Gui Xie;Liming Chen
中科院分区：
文献类型：
--
作者：
Ling Huang;Jun Zhang;Bo Wei;Shuangyang Chen;Si-jun Zhu;Weiguan Qi;Xiaoying Pei;Lulu Li;Weiguang Liu;Yuzhi Wang;Xiaojun Xu;Lan-Gui Xie;Liming Chen
缺乏MHC-II正在成为癌症免疫逃避的一个致病因素，并且小分子MHC-II诱导剂的开发是一个未满足的临床需求。在这里，我们确定了三个MHC-II诱导剂，包括降植烷及其两个上级衍生物，有效地诱导乳腺癌细胞中的MHC-II表达，并有效地抑制乳腺癌的发展。我们的数据表明，MHC-II在促进癌症的免疫检测以增加T细胞的肿瘤浸润和增强抗癌免疫中是中心的。通过发现脂肪酸合成酶（FATCH）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点，我们证明了逃避免疫检测和癌症代谢重编程与脂肪酸介导的MHC-II沉默直接相关。总的来说，我们确定了三种MHC-II诱导剂，并说明了由超活化脂肪酸合成引起的MHC-II缺乏限制免疫检测是癌症发展的潜在普遍机制。
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.