Analysis of immune status and prognostic model incorporating lactic acid metabolism-associated genes.

Abstract

Background: Cancer development is intricately linked with metabolic dysregulation, including lactic acid metabolism, which plays a pivotal role in tumor progression and immune evasion. However, its specific implications in gastric adenocarcinoma (STAD) remain unclear. This study introduces a novel methodology to evaluate lactic acid metabolism comprehensively in STAD, aiming to elucidate its prognostic significance and impact on immunotherapy efficacy. Targeted therapies directed at key lactic acid metabolism genes (LMGs) identified within the tumor microenvironment (TME) hold promise for personalized treatment strategies.

Methods: Lactic acid metabolism patterns were assessed in 415 STAD patients using a panel of 21 LMGs. Cox regression and Lasso regression analyses were employed to develop a predictive risk model based on differentially expressed genes (DEGs). Validation of the model was conducted using independent cohorts from the GEO and TCGA databases, as well as additional datasets focused on immunotherapy responses. Further investigations into TME dynamics of lactic acid metabolism included functional assays targeting SLC16A3, a pivotal gene identified through our analyses.

Results: Patients were stratified into distinct risk groups based on their lactic acid metabolism profiles. Low-risk patients exhibited attenuated lactic acid metabolism, correlating with favorable clinical outcomes characterized by prolonged survival and enhanced responsiveness to immunotherapy. Notably, tumor cells within the TME demonstrated heightened levels of active lactic acid metabolism, particularly impacting tumor-infiltrating lymphocytes such as CD8 + T cells and regulatory T cells. Mechanistically, SLC16A3 emerged as a critical regulator promoting STAD cell proliferation, invasion, and migration while modulating the metabolic landscape.

Conclusion: This study underscores the prognostic value of a lactic acid metabolism-based model in STAD, providing insights into its potential as a predictive biomarker for patient stratification and therapeutic targeting. The findings highlight SLC16A3 as a promising candidate for therapeutic intervention aimed at modulating lactic acid metabolism in the TME, thereby advancing personalized treatment strategies in gastric cancer management.