A Molecular Trimming Strategy for Hypoxia‐Tolerant Photosensitizers With Enhanced cGAS‐STING Activation

ABSTRACT The development of effective photosensitizers for photo‐immunotherapy is highly desirable yet remains challenging, particularly given the prevailing reliance on π‐conjugation extension in conventional molecular design. Herein, we propose a counterintuitive “π‐bridge trimming” strategy to construct high‐performance Ir(III) complexes photosensitizers. Unlike the conventional π‐extension approach, the three‐ring fused TTz‐Ir outperforms its π‐extended five‐ring fused analog TBTz‐Ir in multiple aspects, including molar absorptivity, solubility, photocatalytic activity, and photocytotoxicity. Mechanistic studies revealed that the superior performance of TTz‐Ir stems from its longer triplet‐state lifetime, more efficient charge separation, and transport favoring type I reactive oxygen species (ROS) generation. Upon light irradiation, TTz‐Ir not only produces 1 O 2 via energy transfer, but also efficiently generates type I ROS such as O 2 •− , H 2 O 2 , and •OH, primarily through oxygen reduction reaction (ORR) and water oxidation reaction (WOR) pathways, ensuring robust photocytotoxicity even under hypoxia. These ROS induces mitochondrial and nuclear DNA damage, leading to activation of the cGAS‐STING pathway and robust antitumor immunity. When encapsulated into DSPE‐PEG 2000 ‐Biotin, TTz‐Ir NPs achieve effective tumor accumulation and significant tumor suppression in vivo. This work provides a novel molecular design paradigm and efficient metal complexes for photo‐immunotherapy.