Allosteric inhibition of the tyrosine phosphatase SHP2 enhances the anti-tumor immunity of interferon α through induction of caspase-1-mediated pyroptosis in renal cancer

[Display omitted] •SHP099 enhances the anti-proliferative effect of IFNα on RCC in vitro and in vivo.•SHP099 stimulates caspase-1 expression by activating NF-κB signaling.•SHP099 stimulates NLRP3 inflammasome activation via mitochondrial ANT1.•SHP099 enhances anti-tumor immunity induced by IFNα in vitro and in vivo. Interferon alpha (IFNα) leads to therapeutic effects on various tumors, especially renal cell cancer (RCC), by directly protecting against tumors cell proliferation or indirectly inducing an anti-tumor immune response. However, new combination therapies are needed to enhance the efficacy of IFNα and reduce its adverse effects during long-term treatment. In this study, we found that the anti-proliferative effects of IFNα on RCC cells in vitro and in vivo were greater after the allosteric inhibition of SHP2 by SHP099 than after treatment with enzymatic inhibitors of SHP2. SHP099 increased IFNα-induced pro-caspase-1 expression in RCC cells, activated the NLRP3 inflammasome, and induced pyroptosis. Mechanistically, SHP099 not only increased the expression of NLRP3 inflammasome components via the NF-κB signaling pathway, but also further activated the NLRP3 inflammasome by regulating mitochondrial homeostasis through ANT1-mediated reactive oxygen species modulation. Allosteric inhibition of SHP2 by SHP099 also potently enhanced the anti-tumor immunity induced by IFNα by modulating T cell proliferation and infiltration in vitro and in vivo. These results reveal the new function of SHP2 in NLRP3 inflammasome activation and pyroptosis in RCC and provide a basis for further investigating the combination of allosteric SHP2 inhibitors with IFNα in cancer immunotherapy.