MHC Class II and Beyond: Complex Role of CD74 in Cancer

Invariant chain, also known as CD74 when expressed on the plasma membrane, is classically recognized for its role in Major Histocompatibility Complex class II molecule assembly, trafficking, and peptide loading in professional antigen presenting cells. However, recent studies implicate CD74 as a broader regulator of tumor-immune interactions, modulating antigen presentation, cytokine signaling, and immune evasion across diverse cancers. This review synthesizes emerging evidence that CD74 functions as a “master regulator” of antigen presentation in cancer, integrating its canonical chaperone role with its noncanonical role in transcription regulation and in signaling via macrophage migration inhibitory factor. We explore how tumor microenvironmental contexts redefine CD74 biology, influencing antitumor immunity and therapeutic outcomes.