Self-assembled nano-PROTACs potentiate colorectal cancer immunotherapy via downregulating PD-L1 and GPX4 expression.

Ferroptosis, a form of regulated cell death that is iron-dependent and driven by the accumulation of lipid peroxides (LPO), has emerged as a promising avenue for enhancing tumor immunogenicity and augmenting immune checkpoint blockade (ICB) efficacy. In this study, we demonstrated that dBET57, a BRD4-targeting PROTAC, potently suppresses the expression of GPX4, the master negative regulator of ferroptosis, thereby triggering ferroptotic cell death, while concurrently downregulating PD-L1 to reverse immune evasion. Based on this, we developed a self-assembled nano-PROTAC platform, termed dBET@TF, designed to amplify ferroptosis and potentiate colorectal cancer immunotherapy. Specifically, dBET@TF was constructed via self-assembly of dBET57, tannic acid, and Fe3+, which endowed the formulation with acid-responsive drug release capability and significantly improved its intracellular delivery efficiency. Mechanistically, dBET@TF promoted ferroptosis through iron accumulation and GPX4 depletion, triggering robust immunogenic cell death (ICD). Concurrently, BRD4 degradation mediated by dBET@TF durably suppressed PD-L1 expression, reprogramming the tumor microenvironment to foster enhanced immune activation, characterized by increased infiltration of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). As a result, dBET@TF significantly potentiated the therapeutic response to αPD-1 in both primary tumor and experimental lung metastasis models. Overall, this work establishes a novel PROTAC-based therapeutic strategy that leverages BRD4 degradation to amplify ferroptosis and remodel antitumor immunity, offering a promising approach to potentiate colorectal cancer immunotherapy.