PROTAC-based synthetic lethality strategy endogenously activates systemic STING to boost antitumor immunity.

Abstract

Activation of the stimulator of interferon genes (STING) pathway drives natural killer (NK) cells and T cells to orchestrate multidimensional antitumor immune responses. While cytosolic DNA accumulation represents a superior endogenous strategy for STING activation, DNA repair machinery substantially constrains its immunogenic potential. Here, we propose a promising therapeutic strategy that leverages proteolysis-targeting chimera (PROTAC)-mediated degradation of PARP1 [poly(ADP-ribose) polymerase 1] and BRD4 (bromodomain-containing protein 4) to induce synthetic lethality, thereby disrupting DNA repair machinery that drives nuclear-to-cytosolic DNA leakage, surpassing the STING activation threshold to ignite cGAS-STING-mediated innate immunity. Our strategy demonstrates superior antitumor efficacy across multiple tumor models, eliciting robust CD8⁺ T cell- and NK cell-mediated immunity while suppressing pulmonary metastasis progression. This strategic integration of synthetic lethality with an immunogenic stress response establishes a previously unidentified paradigm for expanding broad applications by cGAS-STING-mediated innate immunity.