Work

ENPP1 inhibits the cGAS–STING pathway to mediate immune evasion in EGFR-TKI–resistant non–small cell lung cancer

Year: 2026

Type: article

Abstract: Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated promising clinical efficacy in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Despite substantial progress with EGFR-TKIs, the development of acquired resistance remains a major clinical challenge. Notably, the addition of immune checkpoint blockade after TKI resistance has not resulted in significant survival benefits compared to chemotherapy. In this study, we performed a comprehensive transcriptomic analysis of established osimertinib-resistant tumor models and found that the expression of the ectonucleotide phosphodiesterase ENPP1, a key regulator of extracellular cGAMP signaling, was significantly upregulated in resistant tumors compared to the parental TKI-sensitive NSCLC tumors. Mechanistically, upregulated ENPP1 in resistant cells promoted the hydrolysis of extracellular cGAMP, suppressing the cGAS-STING pathway in immune cells and subsequently impairing immune cell activation and function, thereby promoting immune suppression and tumor progression. Genetic depletion or pharmacological inhibition of ENPP1 enhanced immune cell-mediated cytotoxicity against TKI-resistant tumor cells. Furthermore, the use of ENPP1 inhibitors both in vitro and in vivo enhanced immune cell activity and antitumor efficacy in TKI-resistant lung cancers with high ENPP1 expression. Importantly, these observations were further validated by paired clinical tumor samples, which demonstrated increased ENPP1 expression following the development of acquired EGFR-TKI resistance. Collectively, our study highlights a critical role for ENPP1 in mediating immune evasion through suppression of the cGAMP-STING pathway in the tumor immune microenvironment, supporting ENPP1 as a promising therapeutic target to enhance immunotherapy efficacy in EGFR-TKI-resistant NSCLC.

Source: Cell Death and Differentiation

DOI: 10.1038/s41418-026-01876-6