Excited‐State Structural Distortion of Pentamethine Chains Enhances Singlet Oxygen Generation as a Photoimmunotherapeutic Agent

ABSTRACT The structural design of photosensitizers (PSs) has a significant impact on the intersystem crossing (ISC) and reactive oxygen species (ROS) generation and photodynamic performance. However, current studies of PSs for increasing ROS yield mainly focus on the ground‐state configuration, ignoring the influence of the excited‐state distorted configuration. In this work, we designed a distorted pentamethine chain structure in the excited state with a rotatable, large steric hindrance electron‐withdrawing group (ethylbenzothiazole) in the meso‐position ( Cy‐S‐Y ). Due to a new strategy of structural distortion‐enhanced intersystem crossing (SDE‐ISC), Cy‐S‐Y exhibited a superior capacity for singlet oxygen ( 1 O 2 ) generation ( 1 O 2 quantum yield ( Φ Δ ) = 44.7%) with low light power (3 mW/cm 2 ) in H 2 O, outperforming the Cy‐Br modified with heavy atoms (8.4‐fold). Theoretical calculations confirmed that Cy‐S‐Y had a distorted pentamethine chain structure in the T 2 state, resulting in a small energy gap (Δ E S1‐T2 = ‐0.002 eV) and a large spin‐orbit coupling constant (SOC = 0.29 cm −1 ), thereby promoting efficient ISC. In addition, Cy‐S‐Y ‐mediated photoimmunotherapy promoted damage‐associated molecular patterns (DAMPs) and released immune‐stimulating factors in vitro. As a result, Cy‐S‐Y not only inhibited tumor growth but also improved the immune microenvironment and significantly prolonged survival in a tumor‐bearing mouse model.