Photodynamic enhancement of PROTAC prodrug activation in hypoxic tumors

Available online 14 July 2025

Author links open overlay panel, , , , , Abstract

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. However, the clinical application of PROTACs may be hindered by off-target toxicity resulting from non-tissue-specific protein degradation and ingenious prodrug strategies may open new avenues to addressing this concern. Herein, we propose a light-induced positive feedback strategy to use photodynamic therapy (PDT) to improve the activation efficiency of PROTAC prodrugs, monitor PROTAC release, and combine PROTAC to induce tumor cell apoptosis. In the hypoxic tumor microenvironment, the azo bond in AZO-PRO selectively cleaves, triggering the release of the potent protein degrader PRO and the multifunctional photosensitizer. Once activated, the fluoresce signal of the photosensitizer dramatically recovers, allowing monitoring of prodrug activation. Additionally, upon irradicating the tumor site using near-infrared (NIR) laser, PDT exacerbates tumor hypoxia, further promoting AZO-PRO activation. Our work introduces a novel approach to efficiently track and activate PROTAC prodrugs, enhance their antitumor efficacy, and mitigate off-target systemic toxicity.

Graphical abstractThis study proposed a light-induced positive feedback strategy, using PDT to aggravate tumor hypoxia to promote hypoxia-responsive prodrug activation, and provide real-time feedback on prodrug activation through fluorescence recovery.