Major Histocompatibility Complex class II (MHC II) molecules present tumor antigens to CD4 + T cells, playing a pivotal role in initiating anti-cancer immunity. Recent discoveries of MHC II expression on atypical antigen-presenting cells (APCs) have spurred interest in targeting MHC II for immunotherapy. Emerging therapies seek to enhance MHC II expression in tumors, particularly immunologically "cold" tumors with limited T-cell infiltration, to amplify CD4 + T cell-mediated anti-tumor responses. Clinical advances include MHC II-guided personalized vaccines, immune checkpoint blockade (ICB), and combination strategies showing promising efficacy. This review delineates MHC II-mediated immunoregulatory networks across professional and atypical APCs, explores their potential as biomarkers and therapeutic targets, and discusses predictive models of MHC II-antigen interactions to advance precision oncology. By elucidating the complexity of MHC II-driven immune regulation, this work aims to optimize immunotherapy design, address tumor heterogeneity, and foster tailored therapeutic approaches for diverse cancer types.
Keywords: Atypical antigen-presenting cells; MHC II; Professional antigen-presenting cells; Tumor immunotherapy.
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