Can restoring major histocompatibility complex class I expression overcome immune evasion in brain cancers?

Abstract Loss or downregulation of MHC-I is a frequent mechanism of immune evasion in central nervous system (CNS) cancers, partially driven by an immunologically cold microenvironment. In this short commentary, we issue a call to action for exploring therapeutic strategies of MHC-I expression restoration in brain cancers to improve patient outcomes. We discuss several potential strategies, including targeting the immunosuppressive microenvironment, epigenetic modulation, and gene therapy approaches. We argue that effective MHC-I restoration may require a combinatorial approach that simultaneously boosts both antigen processing and presentation and remodels the tumor microenvironment. Overcoming CNS-specific barriers, such as the blood-brain barrier, is critical for success. We propose that combining MHC-I re-expression with immunotherapy, chemotherapy, and radiotherapy could provide new therapeutic windows for CNS malignancies.