PROTAC‑Mediated HMGCR Depletion Reprograms Lipid Metabolism in Breast Cancer to Potentiate Photoimmunotherapy via Ferroptosis

ABSTRACT Aberrant lipid metabolism characterizes the progression of breast cancer. Statins, the canonical agents for modulating this pathway, have been associated with improved overall survival in patients with triple‐negative breast cancer (TNBC). However, their clinical benefit remains limited because the reversible inhibition of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) elicits a rebound in the mevalonate pathway and enables evasion of ferroptosis. Therefore, we developed a 170 nm self‐assembled nanomedicine (PRO‐P) that integrates an HMGCR‐targeting PROTAC (PRO) with a disulfide‐linked Pyropheophorbide‐a (Ppa) photosensitizer, enabling laser‐gated protein HMGCR degradation and photodynamic stress within one formulation. Under laser irradiation, PRO‐P catalytically depletes HMGCR while generating reactive oxygen species (ROS), collapsing the mevalonate/CoQ10‐GPX4 axis and redirecting lipids into ferroptosis. In 4T1 cells, PRO‐P enhanced cellular uptake by 1.34‐fold and elevated ROS by 9.5‐fold. Following intravenous administration in TNBC xenografts, PRO‐P achieved 92.5% tumor regression, eradicated pulmonary metastases, and elicited no systemic toxicity after single laser exposure. Immune profiling revealed remodeling of the microenvironment, with 2.6‐fold more CD8⁺ Granzyme‐B⁺ T cells, 4.3‐fold more mature dendritic cells, and fewer Tregs, thereby establishing durable memory. PRO‐P exploits multi‐omics–guided HMGCR targeting to convert lipid addiction into a redox–immunologic vulnerability, yielding a low‐toxicity therapy for TNBC and other lipid‐driven cancers.