Single-cell multiomics identifies an ALDH9A1–carnitine signaling axis driving resistance of NSCLC to immunotherapy

Abstract

Significance Although immune checkpoint inhibitors (ICIs) have revolutionized the clinical management of non–small cell lung cancers (NSCLCs), majority of patients ultimately develop primary or acquired resistance, limiting long-term therapeutic benefits. Here, we show that ALDH9A1, the committed enzyme in carnitine biosynthesis, is a previously unrecognized regulator of immune evasion in NSCLC and an important functional contributor to immunosuppressive remodeling and response to anti-PD-1 therapy. This resistance can be overcome by IL-1β neutralization or pharmacologic ALDH9A1 inhibition with DEAB. Clinical analyses further reveal a strong association between dysregulation of the ALDH9A1/IL-1β axis and reduced survival in patients with NSCLC, highlighting this pathway as a promising therapeutic target for next-generation immunotherapy strategies. These findings warrant further investigation into its clinical utility.