CD74 (MHC class II invariant chain) is a non-polymorphic type II transmembrane glycoprotein with diverse immune and pathological functions beyond its classical role as an MHC class II chaperone 1. Primary function: CD74 stabilizes cathepsin L conformation and maintains pools of mature enzyme in endocytic compartments of antigen-presenting cells 2. Mechanism: CD74 serves as a high-affinity cell membrane receptor for macrophage migration inhibitory factor (MIF) and participates in MHC class II protein trafficking 1. Activation of the CD74/CD44 receptor complex triggers multiple intracellular signaling cascades including ERK1/2, PI3K-Akt, NFκB, and AMPK pathways 1. Disease relevance: CD74 regulates T-cell and B-cell development, dendritic cell motility, and macrophage inflammation, with documented roles in liver fibrosis, type I diabetes, and systemic lupus erythematosus 1. Clinical significance: High CD74 expression in tumor-infiltrating cells identifies constitutive interferon-high immunophenotypes predicting immunotherapy response in colorectal cancer, independent of MMR status 3. CD74 supports tumor-infiltrating regulatory T cell accumulation and suppressive function 4. Blocking tumor-associated macrophage-derived CD74 enhances neoadjuvant chemotherapy efficacy with PD-1 blockade in cervical cancer 5, and MIF-CD74 axis inhibition augments radiotherapy response in brain metastasis 6.