RNASEH2C enhances TRAF3IP1 to degrade RAI14 in lysosomes thus hindering macrophage antigen presentation and advancing liver cancer

Abstract Macrophage antigen presentation is crucial for adaptive immunity and maintaining immune balance, including anti-infection, anti-tumor, and inflammation regulation. However, its role in tumor immunomodulation is less understood compared to macrophage polarization. This study explored how Rnaseh2c + macrophages influence hepatocellular carcinoma (HCC) progression using in vitro cell models and mouse tumor models. Single-cell RNA sequencing, immunoblotting, immunofluorescence, immunoprecipitation, and flow cytometry analysis were employed to examine RNASEH2C’s impact on macrophage antigen presentation. Our results indicated that Rnaseh2c + macrophages, which were non-polarized, promoted HCC growth by inhibiting antigen presentation. RNASEH2C facilitated lysosomal degradation of RAI14 by enhancing TRAF3IP1 expression and suppressing the mTOR pathway, with HSC70 and CMTM6 playing opposing roles in RAI14 degradation. RAI14, a skeleton protein, facilitated the macropinocytosis of MHC II molecules and tumor-associated antigen, thus activating Th1 cells in HCC. In conclusion, our study revealed how RNASEH2C mediated RAI14’s lysosomal degradation, offering potential targets and strategies for HCC immunotherapy.