Targeting STING for cancer immunotherapy: From mechanisms to translation

Cancer immunotherapy with immune checkpoint inhibitors has achieved unprecedented success in cancer treatment; However, only a subset of patients achieved clinical benefit from this treatment, underscoring the urgent need to identify new strategies to enhance the clinical efficacy of immune checkpoint inhibitors. Given the essential role of innate immunity in cancer immune surveillance, tremendous effort has been focused on the innate immune pathways that can be pharmacologically modulated to improve the clinical outcome of checkpoint inhibitors. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays essential roles in host defense against cancers. Activation of the cGAS-STING signaling pathway induces the expression of type I interferons and proinflammatory cytokines, culminating in promotion of a robust adaptive antitumor immunity. As part of this innate immune signaling pathway, STING is ubiquitously expressed in immune and nonimmune cells. STING activation has been demonstrated to propagate the cancer immunity cycle, remodel the tumor microenvironment, and ultimately eliminate tumor cells. The immunomodulatory roles of STING enable it to be an appealing target for cancer immunotherapy. As such, STING agonists that are capable of triggering antitumor immune responses have been developed in recent years, and several of them have advanced into clinical trials. In this review, we first give an overview on the STING signaling pathway, then dissect the roles of STING activation in different steps of the cancer immunity cycle and finally discuss the development of STING agonists as well as challenges with STING activation, with the potential to make cancer immunotherapy with STING agonists more effective.