Microtubule polymerization induced by iridium-fullerene photosensitizers for cancer immunotherapy via dual-reactive oxygen species regulation strategy

Abstract

Microtubules (MTs) are key players in cell division, migration, and signaling, and they are regarded as important targets for cancer treatment. In this work, two fullerene (C₆₀)-functionalized Ir(III) complexes (Ir-C₆₀1 and Ir-C₆₀2) are rationally designed as dual reactive oxygen species (ROS) regulators and MT-targeted Type I/II photosensitizers. In the dark, Ir-C₆₀1 and Ir-C₆₀2 serve as ROS scavengers to eliminate O₂•⁻ and •OH, consequently reducing the dark cytotoxicity and reversing dysfunctional T cells. Due to the efficiently populated C₆₀-localized intraligand triplet state, Ir-C₆₀1 and Ir-C₆₀2 can be excited by green light (525 nm) to produce O₂•⁻ and •OONO⁻ (Type I) and ¹O₂ (Type II) to overcome tumor hypoxia. Moreover, Ir-C₆₀1 is also able to photooxidize tubulin, consequently interfering with the cellular cytoskeleton structures, inducing immunogenic cell death and inhibiting cell proliferation and migration. Finally, Ir-C₆₀1 exhibits promising photo-immunotherapeutic effects both in vitro and in vivo. In all, we report here the first MT stabilizing photosensitizer performing through Type I/II photodynamic therapy pathways, which provides insights into the rational design of new photo-immunotherapeutic agents targeting specific biomolecules.