Microsatellite-instable tumor hijacks TREX1 to escape immunosurveillance by suppressing tumor intrinsic cGAS induced antitumor immunity (PRJCA024292)
As promising predictive biomarkers, mismatch repair deficiency (dMMR), and microsatellite instability-high (MSI-H) guide the clinical application of immune checkpoint blockade (ICB) therapies regardless of tumor location and tumor type. However, it is worth to emphasize that about half of dMMR/MSI-H CRCs still failed to response effectively to the ICB immunotherapy and most primary responder also lose of the sensitivity to ICBs overtime, indicating the urgency to identify the valuable targets for cancer immunotherapy. Herein, we observed that dMMR tumors-derived type I interferon (IFN-I) upregulates endogenous 3' repair exonuclease 1(TREX1) to restrict antitumor immunity. Mechanistically, loss of TREX1 in dMMR tumors further triggers tumor intrinsic cGAS-STING activation that contributes to provoking CD8+T cells mediated antitumor immunity. Depleting CD8+T cells or tumor intrinsic cGAS-STING axis abolishes the effect of TREX1-deficient in MSI-H tumor growth. Moreover, loss of dMMR tumor intrinsic TREX1 also help to establish systemic antitumor immunity. This indicates that MSI-H tumors hijack TREX1, as one of the major barriers of tumor endogenous innate sensing pathway, to suppress the tumor intrinsic cGAS-STING mediated antitumor immunity. Overall, our study suggests that TREX1 could be a promising target in MSI tumor to provoke antitumor immunity.