CD74 regulates antitumor immunity in melanoma by reprogramming dendritic cell immunogenicity and migration

Metastatic cutaneous melanoma remains a major therapeutic challenge, as many patients fail to respond or relapse following immune checkpoint therapy. The function of CD74, originally described as an MHC-II chaperone and receptor for macrophage migration inhibitory factor, remains poorly understood in tumor immunity. In this study, we show that systemic CD74 deletion in a syngeneic melanoma model significantly delayed tumor growth and reshaped the tumor immune microenvironment, and synergized with immune checkpoint blockade. Tumors in Cd74-/- mice had more effector and memory CD8+ T cells producing IFN-{gamma} and granzyme B than in control mice. Loss of CD74 promoted expansion of migratory cDC1s with elevated MHC-I and CCR7 expression. Cd74-/- professional antigen presenting cells increased cross-priming capacity for tumor-derived antigens in vivo and in vitro. Absence of CD74 induced the expression of CCR7, a key lymph node homing molecule, on cDCs and enhanced their ability to migrate towards the CCL19 ligand in single cell tracking analyses. These findings identify CD74 as a regulator of dendritic cell function and a promising therapeutic target to improve melanoma immunogenicity. One Sentence SummaryCD74 restrains cross-priming and migration capacity of dendritic cells, leading to impaired CD8+ T-cell infiltration and activation in tumor immunity.