Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.

Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.