Cancer cell-autonomous cGAS-STING response confers drug resistance

Abstract

As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.

DNA sensing of dendritic cells in cancer immunotherapy

“…Unfortunately, activation of intrinsic DNA sensing in tumors sometimes does not mean increased antitumor immunity. A more recent study demonstrated that intracellular cGAS-STING-activated cancer cells can resist chemotherapy drug-induced stress by hijacking evolutionarily conserved NF-κB inflammatory signaling (Lv et al, 2023). Moreover, IRF3, a downstream transcription factor of the cGAS-STING pathway, directly augmented PD-L1 transcription in hepatocellular carcinoma cells following radiation exposure.…”