Despite advancements in cancer immunotherapy, challenges such as tumor immune escape, immunosuppressive tumor microenvironment (TME), and resistance to immune checkpoint blockade (ICB) limit its broad application. Dysregulated expression of major histocompatibility complex class II (MHC II) enables tumor cells to evade immune surveillance, while its normal function in antigen presentation to CD4 +T cells is critical for initiating anti-tumor immunity and immune memory. MHC II is primarily expressed on professional antigen-presenting cells (APCs), including dendritic cells and macrophages, but emerging evidence highlights its presence on atypical APCs (e.g., tumor cells, cancer-associated fibroblasts), which process MHC II-restricted tumor antigens.

An in-depth exploration of MHC II expression and function on atypical APCs will broaden our understanding of tumor immune escape mechanisms and responses to immunotherapy. The regulation of MHC II involves cytokines, transcriptional/post-transcriptional modifications, and tumor metabolic states, forming a complex network influencing immune activation or suppression in the TME. Recent strategies leveraging MHC II include: Identifying MHC II-restricted tumor antigens for vaccine development (Barker et al., 2023); Enhancing MHC II expression and antigen presentation via genetic engineering (e.g., CIITA transfection) or pharmacological agents (e.g., IFN-γ, HDAC inhibitors); Combining MHC II-targeted therapies with immunomodulators (e.g., ICB, CAR-T) to overcome TME immunosuppression (Luo et al., 2024, Qiu et al., 2024). Additionally, MHC II expression patterns in immune cells may serve as prognostic biomarkers, while computational tools for predicting MHC II-peptide interactions and TCR specificity offer new avenues for personalized therapies.

This review synthesizes the dual roles of MHC II in immune evasion and activation, its regulatory mechanisms in professional/atypical APCs, and current therapeutic strategies. It underscores the potential of MHC II as a therapeutic target and biomarker while addressing challenges in epitope prediction and TCR screening, paving the way for next-generation immunotherapies.