Macrophage NPM1 drives anti-tumor immunity via the STAT3-CCRL2 axis.

BACKGROUND: Although nucleophosmin (NPM1) is a well-characterized oncogene in acute myeloid leukemia, much less is known about its role in solid tumor immunity. Here, we examined the function of NPM1 in regulating anti-tumor immunity within the tumor microenvironment. METHODS: The proportion and functional changes of macrophages and T cells were detected by flow cytometry, the downstream regulatory genes of NPM1 were detected by RNA-seq, the binding ability of NPM1 and STAT3 was analyzed by Chip and luciferase assay. RESULTS: NPM1 inhibition or genetic deficiency promoted tumor growth in MC38 colon cancer and LLC lung cancer mice models. Npm1+/- mice exhibited enhanced infiltration and polarization of immunosuppressive M2-like tumor-associated macrophages (TAMs) and impaired CD8+ T cell function. Mechanistically, NPM1 bound to p-TAT3/STAT3 and promoted transcription of CCRL2, a key regulator of macrophage polarization. Overexpression of Npm1 in mice suppressed tumor growth, reduced M2 TAMs polarization, and enhanced CD8+ T cell-mediated anti-tumor immunity. CONCLUSION: Our findings revealed that NPM1 protects against tumor progression by regulating TAMs polarization and T cell function via the STAT3-CCRL2 axis.