Metabolic reprogramming signature predicts immunotherapy efficacy in lung adenocarcinoma: Targeting SLC25A1 to overcome immune resistance

Abstract

<sec><b>Objective</b>Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Despite significant advances in immunotherapy, treatment responses vary substantially among individuals. Metabolic reprogramming, as a hallmark of cancer, plays a crucial role in tumor progression and immune evasion. However, the interplay between metabolic features and tumor immune microenvironment in LUAD remains to be systematically elucidated. </sec><sec><b>Methods</b>We analyzed data from 1,231 LUAD patients across seven global cohorts and developed an integrated Metabolism-Related Signature (iMRS) using machine learning approaches based on 114 metabolic features. The signature’s ability to predict immunotherapy response was validated using 9 immunotherapy cohorts (n=712, including LUAD, melanoma, and glioma). An in-house LUAD tissue cohort (n=146) confirmed the prognostic significance of <i>SLC25A1</i>, a key gene within the signature, and its spatial relationship with immune cells. <i>In vivo</i> and <i>in vitro</i> experiments investigated <i>SLC25A1</i>’s role in cancer promotion, immune exclusion, and its impact on programmed cell death protein 1 (PD-1) therapy efficacy. </sec><sec><b>Results</b>iMRS demonstrated superior prognostic performance in LUAD patients, outperforming 129 published LUAD signatures. In immunotherapy cohorts, responders showed significantly lower iMRS scores. High iMRS was associated with reduced immune activity and “cold” tumor characteristics. <i>SLC25A1</i> (correlation coefficient=0.54, P&lt;0.05), a key gene in the signature, showed the highest expression in CD8 desert phenotype and correlated with poor prognosis. Multiplexed immunofluorescence revealed exclusion patterns between <i>SLC25A1</i> and immune cells (CD4+ T cells and CD20+ B cells). <i>SLC25A1</i> knockdown reduced lung metastasis and enhanced anti-PD-1 efficacy by increasing CD8+ T cell abundance and cytotoxicity [increased interferon-γ (IFN-γ)+/GZMB+ CD8+ T cells]. </sec><sec><b>Conclusions</b>iMRS provides personalized immunotherapy prediction for LUAD patients. <i>SLC25A1</i>, identified as a novel immune-exclusion related oncogene, represents a promising therapeutic target for LUAD treatment.</sec>

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