Re-expression of MHC-I to treat CNS cancers

Copyright: © 2026 Yuzhalin. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Immunologically “cold” malignant tumors of the central nervous system (CNS) evade immune surveillance largely through downregulation or loss of major histocompatibility complex class I (MHC-I), impairing CD8+ T cell-mediated elimination and contributing to poor prognosis. I discuss multiple strategies to restore MHC-I expression in brain cancers, including epigenetic modulation with histone deacetylase (HDAC) and DNA methyltransferase inhibitors, adeno-associated virus (AAV)-based gene therapy for direct human leukocyte antigen (HLA) class I or transcription factor delivery, and modulation of the tumor microenvironment to enhance antigen presentation. In addition, targeting autophagy and addressing genetic HLA losses are discussed as critical considerations. Effective MHC-I restoration may require integrated approaches that also enhance antigen processing and neoantigen presentation. Overcoming CNS-specific barriers and combining MHC-I re-expression with immunotherapy and chemoradiotherapy could unlock new therapeutic avenues against CNS malignancies.