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

Abstract

Highlights: What are the main findings? CD74 links MHC class II antigen presentation with signaling and transcriptional regulation in cancer. Dysregulated CD74 processing and MIF-CD74 signaling contribute to tumor immune evasion. What are the implication of the main findings? CD74 shapes the tumor immune microenvironment and antitumor immune responses. CD74 represents a biomarker and therapeutic target for cancer immunotherapy. 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.