The role of the cGAS-STING pathway in radiation-induced lung injury: mechanisms and therapeutic perspective

Abstract In contemporary oncologic care, ionizing radiation (IR) is a crucial therapeutic modality for a wide range of cancers. However, a significant challenge in thoracic radiotherapy is the unavoidable exposure of adjacent lung tissue, which has a high intrinsic radiosensitivity. This often results in radiation-induced lung injury (RILI), a common and dose-limiting clinical complication. The pathogenesis of RILI is mechanistically associated with IR-induced cytosolic double-strand DNA (dsDNA) breaks, which strongly enhance the activation of the stimulator of interferon genes (STING) signaling pathway. Nevertheless, the persistent activation of this innate immune cascade leads to an excessive production of type I interferons (IFN-α/β) and numerous pro-inflammatory cytokines. We summarize the current evidence on the role of IR-stimulated cyclic GMP-AMP synthase (cGAS)-STING signaling in driving the pathological progression from radiation pneumonitis to pulmonary fibrosis. The elucidation of IR-mediated cGAS-STING signaling in RILI is crucial for developing innovative adjuvant strategies aimed at improving the therapeutic ratio of radiotherapy by simultaneously enhancing tumor cell kill and reducing normal lung injury. Additionally, this review discusses the emergence of cGAS-STING inhibitors as a promising new approach for managing RILI. We aim to provide a critical framework for exploring novel RILI management strategies and to inform the rational development of therapeutics targeting the cGAS-STING axis.