Conventional DNA-Damaging Cancer Therapies and Emerging cGAS-STING Activation: A Review and Perspectives Regarding Immunotherapeutic Potential

SIMPLE SUMMARY: The cGAS-STING cellular signaling pathway is a key member of the DNA damage response, whose role is to repair the DNA damage that occurs naturally during the life of a cell. Interestingly, cGAS-STING is known to promote immune responses against tumors, and is being explored for its potential use in cancer immunotherapy applications. The DNA damage caused by traditional cancer treatments such as radiation and chemotherapy is one of the main ways in which cancer cells are eradicated, and is increasingly being linked with cGAS-STING activation. In this review, we summarize the many reports of cGAS-STING activation by different conventional cancer therapies, highlighting the roles of their targets in the DNA damage response. As part of the review, we discuss an emerging “chemoimmunotherapy” concept where the DNA-damaging activity of these conventional therapies can potentially be exploited for its beneficial stimulation of anticancer immune responses by way of cGAS-STING activation. The potential advantages of such an approach are highlighted, and it becomes clear that targeted nanoparticle delivery systems will be critical in minimizing the associated immunotoxic and inflammatory activities of the entrapped chemotherapeutics. ABSTRACT: Many traditional cancer treatments such as radiation and chemotherapy are known to induce cellular DNA damage as part of their cytotoxic activity. The cGAS-STING signaling axis, a key member of the DNA damage response that acts as a sensor of foreign or aberrant cytosolic DNA, is helping to rationalize the DNA-damaging activity of these treatments and their emerging immunostimulatory capacity. Moreover, cGAS-STING, which is attracting considerable attention for its ability to promote antitumor immune responses, may fundamentally be able to address many of the barriers limiting the success of cancer immunotherapy strategies, including the immunosuppressive tumor microenvironment. Herein, we review the traditional cancer therapies that have been linked with cGAS-STING activation, highlighting their targets with respect to their role and function in the DNA damage response. As part of the review, an emerging “chemoimmunotherapy” concept whereby DNA-damaging agents are used for the indirect activation of STING is discussed as an alternative to the direct molecular agonism strategies that are in development, but have yet to achieve clinical approval. The potential of this approach to address some of the inherent and emerging limitations of cGAS-STING signaling in cancer immunotherapy is also discussed. Ultimately, it is becoming clear that in order to successfully employ the immunotherapeutic potential of the cGAS-STING axis, a balance between its contrasting antitumor and protumor/inflammatory activities will need to be achieved.