Abstract
Stimulator of interferon genes (STING) has emerged as a critical cancer immunotherapy target. However, no STING agonist has advanced beyond phase I/II clinical trials, as obstacles center around applying STING agonism to the appropriate clinical context, retaining it in the tumor microenvironment (TME), and limiting its T cell toxicity. Using triple-negative breast cancer (TNBC), we identify defective STING turnover as a cancer state promoting hypersensitivity to STING agonism. We also repurpose a US Food and Drug Administration (FDA)-approved polyethylene glycol (PEG) biopsy marker to deliver STING agonists in a controlled release fashion into the TME. However, STING agonist-induced T cell toxicity limits robust endogenous clonal T cell response, which can be overcome by sequential co-delivery of the STING agonists with CAR T cell therapy using the same PEG marker, eradicating orthotopic TNBC in mouse models while also controlling distant disease. These findings identify a highly translatable platform to combine STING agonists with CAR T cell therapy locally for TNBC and potentially other solid cancers.