Orchestrating cell cycle arrest and innate immune sensing for synergistic radiotherapy and immunotherapy against non-small cell lung cancer

Radiotherapy combined with immunotherapy is a pivotal strategy for non-small cell lung cancer; yet, its efficacy is severely compromised by tumor heterogeneity and insufficient innate immune activation. Herein, a tumor microenvironment responsive GSK@BSA-MnO₂ nanoplatform is engineered to spatiotemporally synchronize cell cycle arrest with cGAS-STING activation. Upon glutathione triggered degradation, the nanoplatform releases the PLK1 inhibitor GSK461364 and Mn²⁺ ions. Mechanistically, GSK461364 enforces G2/M arrest, profoundly amplifying radiation-induced DNA damage and immunogenic cell death. Crucially, this enriched cytosolic DNA pool is concurrently sensed by cGAS-STING pathway, which is vigorously sensitized by the Mn²⁺ generated locally, culminating in robust type I interferon secretion. This synergistic modulation effectively remodels the immunosuppressive microenvironment, increases CD8⁺ T cell infiltration and induces a strong abscopal effect against metastatic lesions. Collectively, combining cell cycle arrest with innate immune activation is a promising strategy to improve the efficacy of radio-immunotherapy.