Rational design of a V-shaped DNA-targeted photosensitizer enables endogenous DNA damage-driven cGAS-STING activation and systemic antitumor immunity.

Abstract

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central driver of antitumor immunity, yet its safe and efficient activation in solid tumors remains challenging. Here we report a V-shaped photosensitizer, 2C6, that functions as an in situ DNA-fragmentation agent by directly targeting double-stranded DNA (dsDNA). Owing to its A-π-D-π-A molecular framework, 2C6 exhibits efficient reactive oxygen species (ROS) generation under low-power white-light irradiation. Photoactivation of 2C6 induces concurrent mitochondrial and nuclear DNA damage, leading to the accumulation of oxidized dsDNA fragments in the cytosol, which is closely associated with activation of the cGAS-STING signaling pathway. In parallel, 2C6-PDT induces pyroptosis and immunogenic cell death (ICD), as evidenced by elevated levels of pyroptosis-associated markers (including NLRP3, cleaved caspase-1, and GSDMD), along with features of ICD such as CRT exposure, ATP secretion, and HMGB1 release. In a murine 4T1 triple-negative breast cancer (TNBC) postsurgical residual model, a single intraoperative 2C6-PDT prevented local tumor recurrence, established immune memory within the observation period, and suppressed distant tumor growth and lung metastasis without immunoadjuvants. Collectively, 2C6 couples photoinduced DNA damage to cytosolic dsDNA sensing, type I interferon signaling, and adaptive immune activation through a defined cascade encompassing DNA damage, dsDNA accumulation, cGAS-STING engagement, inflammatory signaling, and immune-cell infiltration. Together, these findings demonstrate that rationally engineered DNA-targeted photosensitizers can convert localized photodynamic tumor ablation into a systemic photoimmunotherapeutic response, providing a strategy to transform immunologically "cold" tumors into immune-responsive states.