Host STING-dependent MDSC mobilization drives extrinsic radiation resistance

TLDR

Radiotherapy activates innate and adaptive immunity through host STING, yet tumors can develop radioresistance that leads to relapse. The study investigates how radiation‑induced STING activation drives immunosuppressive M‑MDSC infiltration, resulting in tumor radioresistance. STING/type I interferon signaling recruits CCR2‑dependent myeloid cells, creating suppressive inflammation that underlies extrinsic radioresistance. Blocking CCR2 with genetic knockout or antibody prevents MDSC infiltration, reduces STING‑mediated immunosuppression, and enhances the anti‑tumor effects of STING agonists and radiotherapy, a strategy that also shows promise in humans.

Abstract

Abstract Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. However, radioresistance in irradiated tumors can also develop, resulting in relapse. Here we report a mechanism by which extrinsic resistance develops after local ablative radiation that relies on the immunosuppressive action of STING. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration. Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy. We propose that radiation-induced STING activation is immunosuppressive due to (monocytic) M-MDSC infiltration, which results in tumor radioresistance. Furthermore, the immunosuppressive effects of radiotherapy and STING agonists can be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.