A dual PROTAC nanocarrier amplifies DNA damage and STING activation for cancer immunotherapy

The cytoplasmic accumulation of damaged DNA to activate the STING pathway has emerged as a promising strategy to enhance tumor immunogenicity and improve the efficacy of immune checkpoint blockade (ICB) therapy. Herein, a stimuli-responsive and dual PROTAC-embedded immunoactivator (denoted as Sd@Lip) is developed to potentiate ICB through amplified DNA damage and robust STING activation. Sd@Lip comprises an acid-sensitive liposomal nanocarrier co-encapsulating two targeted degraders of dBET1 (a BRD4 degrader) and SK-575 (a PARP1 degrader), which enhances drug solubility, stability, and enable precise stoichiometric co-delivery. Mechanistically, Sd@Lip enhances DNA damage by simultaneously disrupting both nonhomologous end joining (NHEJ) and homologous recombination (HR) repair pathways, leading to cytoplasmic DNA accumulation that activates STING signaling, induces proinflammatory cytokine release and enhances infiltration of immune effector cells. This immunogenic cascade promotes the recruitment of natural killer (NK) cells and cytotoxic T lymphocytes into the tumor microenvironment, thereby significantly augmenting the therapeutic efficacy of ICB against both primary and metastatic breast tumors. Collectively, this study highlights a synergistic PARP1 and BRD4 degradation strategy to induce immunostimulatory DNA damage, offering a compelling approach to improve outcomes in breast cancer immunotherapy.