A hybrid nanoadjuvant cascading activation of the cGAS-STING-IFN-Ⅰ pathway to enhance radio-immunotherapy.

The cGAS-STING signaling pathway is crucial for radiotherapy (RT)-induced immune modulation. However, under hypoxic conditions, reduced DNA damage and enhanced DNA damage repair (DDR) lead to lower cytosolic double-stranded DNA (dsDNA) levels, making standard RT doses inadequate for sustained cGAS-STING activation, resulting in transient immune responses. In this study, we developed the As-Mn@MnO2@Alb nanosystem as a potent radiosensitizer and cGAS-STING pathway amplifier. Arsenic trioxide (ATO)-mediated radiosensitization suppresses DDR, enhances immunogenic cell death, and increases tumor-associated antigens and cytosolic dsDNA levels. Concurrently, degradable MnO2 releases Mn2+ in tumors, boosting cGAS recognition and sensitivity, while generating oxygen to alleviate hypoxia and improve RT efficacy. The synchronized delivery of Mn2+ and accumulated cytosolic dsDNA amplifies cGAS-STING activation, promoting dendritic cell (DC) maturation, enhancing CD8+ T cell infiltration, reducing immunosuppressive Treg infiltration, and significantly inhibiting both irradiated local tumors and non-irradiated distal CRC tumors while inducing robust immune memory effects, all with no notable toxicity. This study demonstrates that effective RT sensitization, coupled with synchronized STING activation, represents a robust strategy to overcome radio-immunotherapy resistance in colorectal cancer.