Iterative Optimization of Photoactivatable BRD4 Degraders for Aging‐Amplified Immunotherapy in Patient‐Derived Lung Cancer Organoids

ABSTRACT 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 two‐photon‐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 ferro‐aging, 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.