Photoredox-Mediated Immunotherapy Utilizing Rhenium(I) Photocatalysts with Electron Donor–Acceptor–Donor Configuration

The hypoxic environment of solid tumors significantly
diminishes
the therapeutic efficacy of oxygen-dependent photodynamic therapy.
Developing efficient photosensitizers that operate via photoredox catalysis presents a promising strategy to overcome this
challenge. Herein, we report the rational design of two rhenium(I)
tricarbonyl complexes (Re-TPO and Re-TP)
with electron donor–acceptor–donor configuration. Notably, Re-TP exhibits aggregation-induced emission properties and
enhanced spin–orbit coupling compared to Re-TPO, thus exhibiting promoted photosensitizing capability. In addition
to generating type I and II reactive oxygen species, the excited Re-TP facilitates the photocatalytic oxidation of NADH to
NAD+ and the photoreduction of pyruvic acid to lactic acid.
This metabolic intervention triggers PD-L1-linked immune responses
and disrupts tumor redox balance, leading to ferroptosis and immunogenic
cell death. The combined ferroptosis and immunotherapy effects significantly
suppress both primary and distant B16 tumors. This investigation provides
a compelling model for designing efficient metal-based PSs for photoredox-mediated
photoimmunotherapy against hypoxic tumors.