MG53 suppresses IRF7 to reprogram macrophages and promote antitumor immunity in pancreatic ductal adenocarcinoma

In pancreatic ductal adenocarcinoma (PDAC), the desmoplastic stroma and immunosuppressive tumor microenvironment (TME) present barriers to immunotherapy. Here, we show that MG53 (TRIM72) is a critical regulator of macrophage fate and anti-tumor immunity; its myeloid-specific depletion accelerates PDAC progression by locking macrophages into a suppressive state, whereas its restoration dismantles the immunosuppressive TME. Mechanistically, MG53 binds the Irf7 locus to suppress the pro-tumorigenic myeloid program, and concomitant IRF7 deletion reverses the phenotype of MG53-deficient models. Clinically, an MG53-low/IRF7-high TAM signature correlates with reduced survival across gastrointestinal malignancies, particularly within PDAC cohorts. Using a macrophage-tropic mRNA-LNP platform to restore MG53 expression in vivo, thereby suppressing tumor growth and enhancing antitumor immune activity in PDAC. Our findings demonstrate that MG53 functions as a myeloid checkpoint regulator and suggest mRNA-based reprogramming as a potential strategy to address therapeutic resistance in PDAC.