Mechanisms of low MHC I expression and strategies for targeting MHC I with small molecules in cancer immunotherapy
Shijia Kong, Jie Zhang, Longsheng Wang, Wen Li, Hongjie Guo, Qinjie Weng, Qiaojun He, Honggang Lou, Ling Ding, Bo Yang
Abstract
Major histocompatibility complex (MHC) class I load antigens and present them on the cell surface, which transduces the tumor-associated antigens to CD8 + T cells, activating the acquired immune system. However, many tumors downregulate MHC I expression to evade immune surveillance. The low expression of MHC I not only reduce recognition by- and cytotoxicity of CD8 + T cells, but also seriously weakens the anti-tumor effect of immunotherapy by restoring CD8 + T cells, such as immune checkpoint inhibitors (ICIs). Accumulated evidence suggested that restoring MHC I expression is an effective strategy for enhancing tumor immunotherapy. This review focuses on mechanisms underlying MHC I downregulation include gene deletion and mutation, transcriptional inhibition, reduced mRNA stability, increased protein degradation, and disruption of endocytic trafficking. We also provide a comprehensive review of small molecules that restore or upregulate MHC I expression, as well as clinical trials involving the combination of ICIs and these small molecule drugs. Small molecules can reverse MHC I downregulation or directly upregulate MHC I by regulating epigenetics, enhancing transcription, and improving protein stability, thereby enhancing cancer sensitivity to immunotherapy. • Low MHC I expression allows tumors to evade CD8 + T cells, weakening immunotherapy. • The mechanisms behind low MHC I expression in tumor cells are diverse. • Small molecules can reverse MHC I downregulation or directly upregulate it. • Drugs that reverse or upregulate MHC I can sensitize cancer to immunotherapy.