circATF6 triggers calcium overload to synergize with EGFR-TKI in non-small cell lung cancer via modulation of proteostasis.

Drug-tolerant persister (DTP) cells are a reversible, refractory population that contributes to tumor relapse during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy in non-small cell lung cancer (NSCLC). Targeting the vulnerabilities of DTP cells constitutes an effective strategy to enhance the long-term efficacy of EGFR-TKIs. Here, we identify the circular RNA circATF6, which is specifically downregulated in DTP cells due to regulation by the splicing factor ADAR1. Restoration of circATF6 expression significantly enhances osimertinib (Osi) efficacy both in vitro and in vivo. Mechanistically, circATF6 interacts with the endoplasmic reticulum (ER) chaperone BiP/GRP78, inhibiting the activated adaptive unfolded protein response (UPR). This inhibition disrupts proteostasis, leading to ER fragmentation and Ca overload in the cytoplasm, ultimately triggering apoptosis in DTP cells. Notably, lipid nanoparticle (LNP)-encapsulated circATF6 enhanced the antitumor effects of EGFR-TKI without significant toxicity. Our study provides a therapeutic strategy targeting circATF6 to synergize with EGFR-TKI in NSCLC.