PIKfyve Inhibition Induces Antitumor Immunogenicity by Attenuating STING Trafficking and Lysosomal Degradation

Abstract Significant progress in the application of immune checkpoint blockade for the treatment of multiple types of cancers has been achieved, but its overall response rate and therapeutic efficacy remain unsatisfactory. To address these limitations, the identification of a combinational approach to enhance the therapeutic efficacy of immune checkpoint blockade is needed. The activation of cyclic GMP-AMP synthase–stimulator of IFN genes (cGAS-STING) signaling is critical to the induction of antitumor innate immune responses and is a promising target for the development of combinational immunotherapy. In this study, through the Connectivity Map database and a kinase inhibitor library screen using IFN-stimulated genes as a functional readout, we identified PIKfyve as a negative regulator of cGAS-STING signaling. The inhibition of PIKfyve by the kinase inhibitor YM201636 or genetic ablation elicited the expression of IFN-stimulated genes downstream of cGAS-STING and reshaped the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition conferred sensitivity to the combinational therapy of cisplatin and anti–PD-1, which led to a durable treatment response. Depletion of Sting or CD8+ T cells in B16F10 tumors significantly weakened the synergistic effect of PIKfyve inhibition and cisplatin. Mechanistically, PIKfyve interacts with STING to facilitate its trafficking from endosome to lysosome for degradation, thereby suppressing the STING signaling–mediated antitumor activity. These results highlight the importance of maintaining STING signaling as a direction to augment the efficacy of combinational immunotherapies.