RSK1 reprograms the ubiquitin pathway to promote immune suppression

Although immune checkpoint blockade (ICB) is an effective therapeutic strategy, tumor intrinsic resistance to ICB limits its benefits for a majority of cancer patients. Via multiple in vivo screens, we identified RNF19A as an immune suppressor. RNF19A suppresses ICB efficacy by ubiquitinating cGAS to inhibit the release of type I interferon. Surprisingly, UBE2L6, originally identified as a critical interferon-induced ISG15-conjugating E2 enzyme for ISGylation, functions as the major ubiquitin-conjugating E2 enzyme to enable RNF19A-driven cGAS ubiquitination. Further, RSK1 phosphorylates UBE2L6 to switch its substrate from ISG15 to ubiquitin, thus converting it from an immune response enhancer to a suppressor. In xenograft models, targeting RSK1 or blocking UBE2L6 phosphorylation improves immune response. In patient tissues, the levels of UBE2L6 and its phosphorylation correlate with poor immune infiltration, limited immune and radiation therapy response, and prognosis. Taken together, we demonstrate that RSK1-mediated UBE2L6 phosphorylation and UBE2L6-RNF19A-driven cGAS ubiquitination lead to tumor-intrinsic immune suppression.