2. Academic Validation
  3. PROTAC-based synthetic lethality strategy endogenously activates systemic STING to boost antitumor immunity

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

  • Sci Adv. 2026 Feb 27;12(9):eado7448. doi: 10.1126/sciadv.ado7448.
Ye Liu 1,  Maolin Jiang 1,  Mengchao Ding 1,  Ihsan Ullah 1 2,  Haiyang Wang 3,  Wenjiao Xie 1,  Kewei Wang 4,  Youyong Yuan 1 2 3 5
Affiliations

Affiliations

  • 1 School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 511442, P.R. China.
  • 2 Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, P.R. China.
  • 3 National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P.R. China.
  • 4 Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Engineering Technology Research Center of Drug Carrier of Guangdong, Department of Biomedical Engineering and MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China.
  • 5 Key Laboratory of Biomedical Materials of the Ministry of Education, South China University of Technology, Guangzhou 510006, P. R. China.
PMID: 41758952 DOI: 10.1126/sciadv.ado7448
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.

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