LAUSR

Radiotherapy, a widely used therapeutic strategy for esophageal squamous cell carcinoma (ESCC), is always limited by radioresistance of tumor tissues and side‐effects on normal tissues. Herein, a signature based on four core genes of cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway, is developed to predict prognosis and assess immune cell infiltration, indicating that the cGAS‐STING pathway and radiotherapy efficacy are closely intertwined in ESCC. A novel lipid‐modified manganese diselenide nanoparticle (MnSe2‐lipid) with extraordinarily uniform sphere morphology and tumor microenvironment (TME) responsiveness is developed to simultaneously overcome radioresistance and reduce side‐effects of radiation. The uniform MnSe2 encapsulated lipid effectively achieves tumor accumulation. Octadecyl gallate on surface of MnSe2 forming pH‐responsive metal–phenolic covalent realizes rapid degradation in TME. The released Mn2+ promotes radiosensitivity by generating reactive oxygen species induced by Fenton‐like reaction and activating cGAS‐STING pathway. Spontaneously, selenium strengthens immune response by promoting secretion of cytokines and increasing white blood cells, and performs antioxidant activity to reduce side‐effects of radiotherapy. Overall, this multifunctional remedy which is responsive to TME is capable of providing radiosensitivity by cGAS‐STING pathway‐mediated immunostimulation and chemodynamic therapy, and radioprotection of normal tissues, is highlighted here to optimize ESCC treatment.