Review: The Multifaceted Roles of Lactate in Gastric Cancer and Its Therapeutic Potential

Gastric cancer (GC) remains a leading cause of cancer-related mortality globally, with persistent challenges in overcoming treatment resistance and recurrence. Lactic acid was once considered a metabolic waste, but now it is considered a multifunctional coordinator of GC progression. This review synthesizes emerging evidence on lactate’s multifaceted roles in GC progression, elucidating lactate's multifaceted roles in GC pathogenesis, including its regulation of tumor metabolic heterogeneity, epigenetic reprogramming, and immune microenvironment remodeling. Lactate fosters metabolic symbiosis between glycolytic and oxidative tumor cells, sustains chemoresistance via histone lactylation, RNA methylation, and chromatin phase separation, and promotes the immunosuppressive tumor microenvironment (TME) remodeling and immune evasion by suppressing CD8+ T-cell function and polarizing tumor-associated macrophages (TAMs) towards an M2 phenotype. and polarizing tumor-associated macrophages. Critically, lactate synergizes with Helicobacter pylori (Hp) to form a microbiome-metabolite axis that amplifies bacterial virulence, induces genomic instability, and accelerates malignant transformation. Therapeutic strategies targeting lactate production (LDH-A inhibitors), transport (MCT1/4 blockers), and signaling (epigenetic modulators/lactylation inhibitors) show promise in disrupting these oncogenic circuits. Nanotechnology-driven approaches and microbiome modulation (engineered probiotics) further enhance precision delivery and efficacy. Understanding the interplay between lactate, the tumor microenvironment (TME), and microbial communities offers novel avenues for overcoming therapeutic resistance and improving GC outcomes.