RNF2 induces myeloid-derived suppressor cells chemotaxis and promotes hepatocellular carcinoma progression through the TRAF2-NF-κB signaling axis

RING finger protein 2 (RNF2) has been shown to promote tumor growth in various cancer types. However, the immune regulatory function of RNF2 in the tumor microenvironment is unclear. Here, we report that upregulation of RNF2 is positively correlated with the tumor burden and poor prognosis in hepatocellular carcinoma patients and fosters an immunosuppressive microenvironment with increased MDSCs recruitment, and reduced T cell activation. Mechanistically, RNF2 binds with TRAF2 and directly mediates K63-linked TRAF2 ubiquitination. This modification of TRAF2 enables NF-κB hyperactivation in tumor cells, which subsequently induces CXCL1 transcription to enhance MDSCs migration. Furthermore, RNF2 knockout improves responsiveness to anti-PD-1 therapy in immunocompetent mice, as evidenced by enhancing infiltration of CD8⁺T cells into the tumor and a reduction in MDSC levels. Collectively, our experiments support that perturbing RNF2 and targeting MDSCs may afford therapeutic opportunities for hepatocellular carcinoma interception and prevention.