Cd74, also known as the MHC class II invariant chain (Ii), is a non-polymorphic type II transmembrane glycoprotein. It functions as an MHC class II chaperone, participates in non-MHC II protein trafficking like that of the angiotensin II type I receptor, and serves as a cell membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopachrome tautomerase (D-DT/MIF-2) and bacterial proteins. The activation of the CD74/CD44 receptor complex can lead to the activation of multiple intracellular signal pathways such as ERK1 and 2, the PI3K-Akt signal transduction cascade, NFκB, and the AMP-activated protein kinase (AMPK) pathway. Cd74 is of great biological importance as it regulates T-cell and B-cell developments, dendritic cell motility, macrophage inflammation, and thymic selection [1].

In tumors, genetic deletion of CD74 in human primary regulatory T cells (Tregs) reveals that CD74KO Tregs have major defects in the organization of their actin cytoskeleton and intracellular organelles. Intratumoral CD74KO Tregs show decreased activation, a drop in Foxp3 expression, and low accumulation in the tumor, associated with accelerated tumor rejection in female mice, indicating that CD74 is a specific regulator of tumor-infiltrating Tregs [2]. In cervical cancer, blocking tumor-associated macrophage-derived CD74 enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vivo, suggesting that targeting CD74 can improve the efficacy of neoadjuvant chemotherapy combined with PD-1 blockade [3]. In hepatocellular carcinoma (HCC), CD74 was highly expressed. CD74 expression affected immune cell infiltration levels, regulated myeloid cell differentiation, and patients with high CD74 expression had higher immune scores and better outcomes after immunotherapy [4].

In conclusion, Cd74 plays essential roles in various biological processes, especially in immune-related regulations. The gene knockout studies in Tregs, cervical cancer and HCC models have revealed its significance in tumor-associated immune responses. These findings contribute to understanding the role of Cd74 in tumor biology and potentially guide the development of new therapeutic strategies for related diseases.