SUMOylated IL-33 in the nucleus stabilizes the transcription factor IRF1 in hepatocellular carcinoma cells to promote immune escape

Interleukin-33 (IL-33) functions both as a secreted cytokine and as a nuclear factor, with pleiotropic roles in Cancer and immunity. Here, we explored its role in hepatocellular carcinoma (HCC) and identified that a posttranslational modification altered its nuclear activity and promoted immune escape for HCC. IL-33 abundance was overall decreased but more frequently localized to the nucleus in patient HCC tissues than in normal liver tissues. In human and mouse HCC cells in culture and in vivo, IL-33 overexpression inhibited proliferation and repressed the abundance of programmed death ligand 1 (PD-L1) at the transcriptional level by promoting the ubiquitin-dependent degradation of interferon regulatory factor 1 (IRF1). However, this interaction was disrupted by SUMOylation of IL-33 at Lys⁵⁴ mediated by the E3 ligase RanBP2. IL-33 SUMOylation correlated with its nuclear localization in HCC cells and tumors. An increase in SUMOylated IL-33 in HCC cells in cocultures and in vivo stabilized IRF1 and increased PD-L1 abundance and chemokine IL-8 secretion, which prevented the activation of cytotoxic T cells and promoted the M2 polarization of macrophages, respectively. Mutating the SUMOylation site in IL-33 reversed these effects and suppressed tumor growth. These findings indicate that SUMOylation of nuclear IL-33 in HCC cells impairs antitumor immunity.