Activation of OSMR-STAT3 signaling by AID promotes immune microenvironment remodeling in hepatocellular carcinoma.

Activation-induced cytidine deaminase (AID) is known to contribute to cancer progression, yet its role in immune evasion and tumor microenvironment (TME) associated features in hepatocellular carcinoma (HCC) remains unclear. In this study, we show that AID is associated with immune cell infiltration in the TME of HCC and contributes to the activation of the oncostatin M receptor (OSMR)-STAT3 signaling axis. High AID expression correlated with poor prognosis in HCC patients, while genetic ablation of AID inhibited tumor proliferation and enhanced the infiltration of cytotoxic T cells into the TME. Mechanistically, loss of OSMR abolished the oncogenic effects of AID, indicating that OSMR-dependent signaling is required for AID-driven HCC aggressiveness. Moreover, STAT3 deletion attenuated the pro-tumor functions of AID, affirming the pivotal role of STAT3 signaling. Combined inhibition of the AID-OSMR-STAT3 axis significantly suppressed HCC growth and altered the immune landscape in association with increased infiltration of CD4+ T cells, CD8+ T cells, and B cells. These results identify AID as a regulator of immune evasion in HCC via OSMR-STAT3 activation and suggest that coordinated targeting of this pathway could offer a therapeutic strategy to modulate immunosuppression and enhance anti-tumor immunity, with potential implications for improving current immunotherapies in HCC.