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.

光疗（Phototherapy）以其无创性优势，被广泛应用于肿瘤治疗领域。然而，肿瘤微环境通常处于缺氧状态，活性氧簇（reactive oxygen species, ROS）生成不足，严重制约了其临床应用前景。在此研究中，我们提出区域异构化优化策略，通过精准调控给体-受体（donor-acceptor, D-A）结构的连接位点，合成了四种区域异构的光敏剂。其中，TAF-3不仅具备优异的光稳定性，还拥有超高的I型活性氧生成效率（为亚甲基蓝的4.79倍），光热转换效率达41.7%。TAF-3提升了分子共轭程度，诱导产生适度的分子内电荷转移效应，从而优化了其光学性能与光疗效能，并可触发更强的免疫细胞死亡效应，使术后黑色素瘤复发率降低60%。总体而言，通过精准调控区域异构化，可定制化设计给体-受体型光敏剂的光学属性，为开发适用于光疗的临床光敏剂提供了极具前景的研究方向。