DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

TLDR

Radiotherapy is being studied for its potential to boost immunotherapy responses, yet the mechanisms by which it induces anti‑tumour T cells remain unclear. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy. Cytosolic DNA stimulates secretion of interferon‑β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Trex1 is induced by high‑dose radiation (12–18 Gy), where it degrades cytosolic DNA and dampens interferon‑β production, while avoiding Trex1 induction by lower doses boosts interferon‑β, recruits Batf3‑dependent dendritic cells, and is essential for CD8⁺ T‑cell priming and systemic tumour rejection during checkpoint blockade, establishing Trex1 as an upstream regulator of radiation‑driven anti‑tumour immunity.

Abstract

Abstract Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12–18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8 + T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.