Bulky Group Shaping Cyanine as an Efficient Photosensitizer: A Photo-Inducer for Photodynamic Immunotherapy.

Photodynamic immunotherapy realized with photosensitizers has garnered significant interest in tumor therapy. A complete set of photosensitizer design rules has not been established yet. Herein, the side arms of thio-pentamethine cyanine dye (TCy5) are proven as crucial sites for designing efficient photosensitizers. With precise molecular design, bulky groups on the side arms can shape TCy5 as an efficient photosensitizer compared to TCy5 with alkyl groups. These bulky groups can shape the polymethine chain of TCy5 and regulate the molecular configuration, which narrows the singlet-triplet energy gap and promotes intersystem crossing. Substituting naphthyl groups for alkyl groups increased the singlet oxygen quantum yield of TCy5 from 0 to 41%. Moreover, TCy5 with naphthyl groups efficiently induced immunogenic cell death and activated immune responses in vivo, achieving effective photodynamic immunotherapy. This study serves as a paradigm that the shaping strategy via bulky groups can design efficient photosensitizers for photodynamic immunotherapy.