PIKfyve inhibition synergizes with Cisplatin to provoke antitumor immunogenicity in melanoma by alleviating lysosomal degradation of STING

Immune checkpoint blockade (ICB) has obtained significant progress in treating multiple types of cancers, but its overall response rate and therapeutic efficacies are not yet satisfactory. To fulfil such needs, identification of combinational approach to enhance the therapeutic efficacies of ICB is highly demanded. The activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling is critical to elicit the antitumor innate immune responses and a promising target to develop combinational immunotherapy. Accordingly, the application of STING agonist exhibits potent antitumor functions in preclinical models and is currently tested in clinical trials. However, deregulation of cGAS-STING is frequently observed in cancers and substantially attenuates the efficacies of treatments by harnessing cGAS-STING signaling. Hence, the underlying mechanisms of maintaining intracellular homeostasis of cGAS-STING need to be elucidated. Here we report the identification of PIKfyve as a negative regulator of cGAS-STING signaling. Inhibition of PIKfyve by kinase inhibitor YM201636 or genetic ablation markedly provokes the expression of cGAS-STING downstream IFN-stimulated genes (ISGs) and reschedules the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition confers sensitivity to the combinational therapy of cisplatin and anti-PD1, leading to a durable treatment response. Mechanistically, PIKfyve interacts with STING to promote its lysosomal degradation. These results highlight the importance of maintaining STING homeostasis as a direction to augment the efficacies of combinational immunotherapies