Introduction
Tumors are significant global health challenges with diverse therapeutic strategies, including surgery, chemotherapy, and immunotherapy, offering varying degrees of efficacy1. While surgical resection remains the most frequently used method, immunotherapy has revolutionized primary tumor and metastasis treatment by harnessing the immune system to combat tumors2. Despite these advances, many patients experience intrinsic or acquired resistance to immunotherapy, along with immune-related adverse events (irAEs) that limit broader application of immunotherapy3,4. For example, among melanoma patients treated with ipilimumab at 10 mg/kg, the incidence of severe irAEs reached 37% in the individuals with active metastases and 46% in those receiving post-surgery adjuvant therapy5,6. A study focusing on non-small cell lung cancer (NSCLC) indicated that irAEs associated with programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors correlated with improved radiologic responses, progression-free survival (PFS), and overall survival (OS), which were typically observed approximately 3 months after treatment initiation. As novel immunotherapies and combination regimens continue to emerge, a deeper understanding of the anti-tumor immune response, particularly the mechanisms underlying tumor recognition and immune escape by T cells, are critical for improving outcomes and expanding the applicability of these therapies.
A key mechanism underlying immune escape by tumors is the alteration of antigen-presenting pathways, which reduce tumor visibility to adaptive immune cells7. Central to this process are MHC molecules, which present non-self-peptides (neoantigens) to immune cells. MHC-I and MHC-II molecules are essential elements of the antigen presentation machinery. MHC-I, which present endogenously derived peptides to CD8+ T cells, expressed on virtually all nucleated cells and essential for cytotoxic immune responses. In contrast, MHC-II, which are predominantly expressed by professional antigen-presenting cells (pAPCs), like dendritic cells (DCs), macrophages, and B cells, present exogenous peptides to CD4+ T cells to drive adaptive immunity (Table 1)8-17.
MHC molecule expression is regulated through complex genomic, transcriptomic, and post-translational mechanisms in tumor cells. These processes involve multiple intracellular pathways responsible for antigen processing and presentation. Cytotoxic CD8+ T cells are the primary effectors of immune checkpoint inhibitor (ICI) therapies. In addition, CD4+ T cells are critical for supporting CD8+ T cell activation, promoting memory T cell formation. Emerging evidence underscores the integral function of CD4+ T cells in mediating effective responses to ICIs5,6,8-13,18.
Notably, tumor-specific MHC-II (tsMHC-II) expression, although less frequent, has emerged as a pivotal factor in enhancing anti-tumor immunity. Recent studies have demonstrated a strong correlation between tsMHC-II expression and favorable immunotherapy outcomes, including improved tumor rejection in preclinical models8. MHC-II-restricted CD4+ T cells are critical for supporting CD8+ T cell activation, positioning MHC-II-restricted CD4+ T cells at the forefront of tumor immunotherapy research. This review explores the regulatory mechanisms and latest developments underlying tsMHC-II expression in tumor cells and highlights the tsMHC-II potential to improve the efficacy of current and future immunotherapeutic strategies.
