RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis.

It is well established that interferon (IFN) and tumor necrosis factor (TNF) could synergistically promote antitumor toxicity and avoid resistance of antigen-negative tumors during cancer immunotherapy. The linear ubiquitin chain assembly complex (LUBAC) has been widely known to regulate receptor-interacting protein kinase-1(RIPK1) kinase activity and TNF-mediated cell death during inflammation and embryogenesis. However, whether LUBAC and RIPK1 kinase activity in tumor microenvironment could regulate antitumor immunity are still not very clear. Here, we demonstrated a cancer cell-intrinsic role of LUBAC complex in tumor microenvironment to promote tumorigenesis. Lacking LUBAC component RNF31 in B16 melanoma cells but not immune cells including macrophages or dendritic cells greatly impaired tumor growth by increasing intratumoral CD8+ T cells infiltration. Mechanistically, we found that tumor cells without RNF31 shown severe apoptosis-mediated cell death caused by TNFα/IFNγ in the tumor microenvironment. Most importantly, we found that RNF31 could limit RIPK1 kinase activity and further prevent tumor cell death in a transcription-independent manner, suggesting a crucial role of RIPK1 kinase activity in tumorigenesis. Together, our results demonstrate an essential role of RNF31 and RIPK1 kinase activity in tumorigenesis and imply that RNF31 inhibition could be harnessed to enhance antitumor toxicity during tumor immunotherapy.