Review highlights emerging role of tumor MHC-II in shaping cancer immunotherapy outcomes

Cancer immunotherapy has transformed cancer treatment, yet many patients experience limited or short-lived responses due to immune evasion, tumor heterogeneity, and immune-related adverse events. While the role of MHC-I in antigen presentation and immune surveillance is well established, MHC-II expression in tumor cells has remained far less explored. Recent findings indicate that tumor-expressed MHC-II not only reflects the immune environment but actively directs CD4⁺ T-cell activation, shaping the quality and durability of antitumor immunity. Its involvement in therapeutic resistance and treatment outcomes highlights the need to better understand its regulatory mechanisms and functional implications. Given these challenges, deeper investigation of tumor-cell MHC-II expression and immune function is urgently needed.

Researchers from Zhejiang Cancer Hospital , Hangzhou Institute of Medicine, Chinese Academy of Sciences, have published (DOI: 10.20892/j.issn.2095-3941.2025.0248) a comprehensive review in Cancer Biology & Medicine detailing the biological mechanisms, regulatory networks, and immune impacts of MHC-II expression in tumor cells. Released in 2025, the study integrates molecular, cellular, and multi-omics insights to explain how tumor-specific MHC-II (tsMHC-II) modulates CD4⁺ T-cell responses and influences the effectiveness of immunotherapy. The authors highlight MHC-II as both a mechanistic driver and a translational opportunity for improving patient outcomes.

The review provides an integrated framework explaining how tsMHC-II expression is regulated and how it orchestrates antitumor immunity. Mechanistically, tsMHC-II is controlled by intrinsic oncogenic signaling, including MAPK and NF-κB pathways, which modulate the transcriptional activator CIITA. Extrinsic cytokines—most notably IFN-γ—further enhance MHC-II induction, allowing tumor cells to directly present antigens to CD4⁺ T cells. This interaction is essential for effective CD4⁺ T-cell activation, effector differentiation, and formation of immunologic memory that supports CD8⁺ T-cell responses.

The authors highlight that tsMHC-II strengthens tumor immunogenicity by enabling direct neoantigen presentation, amplifying systemic immune activation. Conversely, loss or downregulation of MHC-II contributes to immune evasion and reduced responsiveness to immune checkpoint blockade. Multi-omics analyses—including single-cell RNA sequencing, spatial transcriptomics, and proteomics—reveal substantial heterogeneity in MHC-II expression across tumor types, underscoring its value for patient stratification.

Together, these findings elevate tsMHC-II from a passive marker to an active determinant of immunotherapy outcomes. The review identifies tsMHC-II as both a predictive biomarker and a therapeutic target, offering new avenues for designing more precise and effective cancer immunotherapies.

According to the authors, unraveling how tumors regulate MHC-II expression is essential for guiding the next phase of immunotherapy innovation. They emphasize that CD4⁺ T cells are central architects of antitumor immunity, and tumor-expressed MHC-II is a key gateway controlling their activation. A clearer understanding of the pathways enhancing or suppressing MHC-II will enable clinicians to better predict therapeutic responses and identify new treatment targets. The authors also note that multi-omics integration will be vital for developing robust MHC-II-based biomarkers and tailoring therapies to individual patients.

The insights outlined in this review hold significant clinical potential. Modulating MHC-II expression could improve patient responses to immune checkpoint therapies, help identify individuals most likely to benefit from treatment, and enable the development of therapies that more effectively activate CD4⁺ T-cell immunity. Targeting MHC-II-associated pathways may also reduce immune-related toxicities by enabling more precise immune activation. Looking forward, incorporating MHC-II into immunotherapy design—whether through biomarker-driven patient selection or direct therapeutic manipulation—could lead to more durable, potent, and personalized cancer treatment strategies.