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

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.