Targeting Heat Shock Proteins and Inhibiting Autophagy to Overcome Photodynamic Therapy Resistance

Excessive reactive oxygen species (ROS) in tumor cells can induce protein misfolding and disrupt cellular signaling pathways, ultimately leading to cell death. However, misfolded proteins can be stabilized or eliminated by chaperone proteins involved in protein quality control, such as heat shock proteins 90 (HSP90) in the endoplasmic reticulum (ER) and mitochondria, as well as through the autophagy process, both of which can contribute to drug resistance. To address these challenges, we develop an organo-iridium photosensitizer, Ir-Pu, which targets HSP90 and investigated its cell death mechanism. Ir-Pu reduces oxidative resistance more effectively compared to the mitochondria-targeted photosensitizer, Ir-Ct. Furthermore, we present biocompatible neutral Ir(III) photosensitizers, B2 and B4, which enable precise ROS control at lysosomes to inhibit autophagy. The biological mechanisms underlying autophagy inhibition via lysosomal oxidation are explored in detail. The anti-tumor efficacy of this precise lysosomal oxidation strategy was further validated in vivo, in drug-resistant pancreatic cancer cells.