SLC2A1 promotes chemo-immunotherapy resistance in lung adenocarcinoma by modulating the AKT signaling pathway.

Chemo-immunotherapy has become a standard treatment for lung adenocarcinoma (LUAD), yet the development of dual resistance to platinum-based chemotherapy and PD-1/PD-L1 blockade severely limits durable clinical benefit. This study aimed to identify a unified molecular regulator that concurrently drives chemoresistance and immune evasion. scRNA-seq of LUAD clinical cohorts was performed to characterize resistance-associated malignant subpopulations, followed by integrative bioinformatics analyses to screen key drivers. Clinical specimen validation and functional experiments, including CCK-8 assays, flow cytometry, transwell migration and western blotting, were conducted to elucidate the underlying mechanisms. We identified a malignant subcluster enriched in non-responsive patients and determined SLC2A1 as the unique overlapping candidate linked to therapeutic failure. Elevated SLC2A1 expression correlated with poor prognosis and enhanced AKT phosphorylation levels. Functionally, SLC2A1 promoted cisplatin resistance, suppressed apoptosis, increased migratory capacity, and upregulated PD-L1 expression, all of which were substantially reversed by AKT inhibition. Notably, this study suggests a previously underappreciated non-canonical role of SLC2A1 as an upstream modulator that coordinates the AKT-PD-L1 axis, thereby potentially integrating chemotherapy resistance and immune escape into a single regulatory framework. These findings provide mechanistic insight into dual refractory LUAD and establish the SLC2A1/AKT axis as a promising therapeutic vulnerability for precision intervention.