Mitotic SENP3 activation couples with cGAS signaling in tumor cells to stimulate anti-tumor immunity

Our previous studies show that the mitotic phosphorylation of SUMO-specific protease 3 (SENP3) can inhibit its de-SUMOylation activity in G2/M phase of the cell cycle. Inhibition of SENP3 plays a critical role in the correct separation of sister chromatids in mitosis. The mutation of mitotic SENP3 phosphorylation causes chromosome instability and promotes tumorigenesis. In this study, we find that the mutation of mitotic SENP3 phosphorylation in tumor cells can suppress tumor growth in immune-competent mouse model. We further detect an increase of CD8(+) T cell infiltration in the tumors, which is essential for the anti-tumor effect in immune-competent mouse model. Moreover, we find that mitotic SENP3 activation increases micronuclei formation, which can activate cGAS signaling-dependent innate immune response. We confirmed that cGAS signaling mediates the mitotic SENP3 activation-induced anti-tumor immunity. We further show that p53 responding to DNA damage activates mitotic SENP3 by inhibiting phosphorylation, and further increases cellular senescence as well as the related innate immune response in tumor cells. Furthermore, TCGA database demonstrates that the SENP3 expression positively correlates with the induction of innate immune response as well as the survival of the p53 mutant pancreatic cancer patients. Together, these data reveal that mitotic SENP3 activation in tumor cells can promote host anti-tumor immune response by coupling with cGAS signaling.