Mechanisms of low MHC I expression and strategies for targeting MHC I with small molecules in cancer immunotherapy.

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.