Regio-isomerization Optimization Strategy for Photosensitizers: Achieving Ultrahigh Type I Reactive Oxygen Species Generation to Enhance Cancer Photoimmunotherapy

Phototherapy,
renowned for its noninvasiveness, is widely employed
in tumor treatment. However, the tumor microenvironment is usually
hypoxic, with insufficient reactive oxygen species (ROS) production,
severely limiting its application. Herein, we introduce a regio-isomerization
optimization strategy and have synthesized four regio-isomeric photosensitizers
featuring a donor–acceptor (D–A) configuration by tactically
varying the linkage sites between D and A. Among them, TAF-3 with
excellent photostability has an ultrahigh type I ROS production efficiency
(4.79 times that of methylene blue) and a photothermal conversion
efficiency of 41.7%. TAF-3 improves the conjugation degree; produces
an appropriate intramolecular charge transfer effect, which enhances
its optical properties and phototherapeutic efficiency; and promotes
a stronger immune cell death effect, reducing postoperative melanoma
recurrence by 60%. Overall, the optical attributes of D–A type
photosensitizers can be tailored through the precision modulation
of regio-isomerization, offering a promising avenue for the advancement
of clinical photosensitizers suitable for phototherapy.