Jinrong Yang, Fa Wang, Shufei Li, Kai Xiong, Taihong Liu*, Yu Chen*, Hui Chao*. Angew. Chem. Int. Ed. 2026, e2645239. https:// doi.org/10.1002/anie.2645239

Cancer remains a major global health threat. Targeted protein degradation (TPD) has revolutionized the modulation of protein function in therapeutic development. Nevertheless, the design of current TPD agents continues to face challenges, including hook effects and, more critically, the frequent lack of spatial and temporal precision required for in vivo applications. Herein, we report a photoactivatable targeted degradation (PATD) strategy and describe the iterative optimization of compound 9, the first twophoton-excited BRD4 photodegrader, achieved through molecular engineering of the photosensitizer core, auxiliary ligands, and linkers. Notably, BRD4 degradation downregulates GPX4 transcription, promoting lipid peroxidation and thereby inducing ferroaging, while simultaneously triggering chemo-aging via histone H3 cleavage, which leads to DNA damage and cell cycle arrest. This dual-aging mechanism accelerates tumor cell senescence, enabling synergistic seno-immunotherapy. Beyond conventional photosensitizers that primarily elicit immunogenic cell death (ICD) alone, complex 9 integrates senescence-driven immunity with ICD-mediated antitumor immunity. This combined immunostimulatory strategy elicits robust systemic antitumor responses and achieves amplified therapeutic efficacy in patient-derived organoids (PDOs), presenting a new paradigm for precision targeted protein degradation in therapy-resistant tumors.

Figure 1. (a) Previously reported PROTACs and PHOTACs. (b) Iterative optimization of the BRD4 photoactivatable degrader and schematic illustration of the mechanism of 9@AuCMs for photoactivatable aging-amplified immunotherapy.

First Author: Yang Jinrong, doctoral candidate, Sun Yat-Sen University

Correspondence Authors: Prof. Liu Taihong, Shaanxi Normal University; Prof. Chen Yu, Sun Yat-Sen University; Prof. Chao Hui, Jinan University and Hunan University of Science and Technology

Full Text Link: https://doi.org/10.1002/anie.2645239