NDRG1‐Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with the tumor microenvironment (TME) playing a critical role in its progression. Metabolic reprogramming, particularly lactate accumulation, drives immune suppression within the TME. Utilizing single-cell RNA sequencing (scRNA-seq) of 30 LUAD samples, genome-wide association studies (GWAS) involving 29,863 patients and 55,586 controls, and clinical data from 220 LUAD patients, we identified N-Myc downstream-regulated gene 1 (NDRG1) as a key pathogenic gene in LUAD, strongly associated with tumor progression and poor prognosis. Mechanistic studies revealed that NDRG1 stabilizes lactate dehydrogenase A (LDHA) by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation. This process fosters immune suppression by inducing M2 macrophage polarization, impairing CD8⁺ T cell function, and upregulating immunosuppressive genes. Furthermore, histone H3K18 lactylation in macrophages exacerbates this immunosuppressive state. Clinically, elevated NDRG1 expression correlates with increased PD-L1 levels, a higher abundance of immunosuppressive macrophages, and reduced CD8⁺ T cell infiltration, contributing to immunotherapy resistance. Conversely, low NDRG1 expression is associated with enhanced CD8⁺ T cell infiltration and improved therapeutic outcomes. Preclinical studies demonstrated targeting NDRG1 suppresses tumor growth, alleviates immune suppression, and boosts anti-PD-L1 efficacy. These findings establish NDRG1 as a critical LUAD regulator and a promising immunotherapy target.