ObjectiveTo systematically summarize the role and molecular basis of lactylation modification in gastric cancer progression (including tumor initiation, development, and drug resistance), and to explore its potential clinical translational value. MethodThe literature published in recent years, both domestically and internationally, focusing on the regulatory mechanisms and clinical applications of lactylation modification in gastric cancer progression was reviewed. ResultsA substantial number of lysine lactylation sites have been systematically identified in gastric cancer. Lactylation modification dynamically regulates the functions of histones (e.g., H3K18la) and non-histone proteins (e.g., PKM2, CPT2) through the “writer–reader–eraser” enzymatic mechanism. It drives cancer cell proliferation, invasion, and metastasis via the NLRP12/HK2 axis and the H3K18la/METTL14/ATF5 pathway. Furthermore, lactylation mediates immune escape by upregulating programmed death-ligand 1 and inducing M2 polarization of macrophages. It also confers resistance to treatments such as oxaliplatin and anlotinib through the BASP1-AS1/LDHA/PCBP2 positive feedback loop and lactate dehydrogenase (LDH) B delactylation. Preclinical studies have demonstrated that targeting glycolysis (inhibiting LDHA), restoring delactylase (SIRT1/2) activity, precisely intervening in the lactylation levels of specific proteins (such as LDHBK58 and TRIM29), or combining with cuproptosis inducers can effectively inhibit tumor growth and sensitize therapeutic responses. Additionally, prognostic models based on lactylation-related genes (e.g., NLRP12) have shown significant potential for clinical outcome assessment. ConclusionsLactylation modification synergistically promotes the malignant progression and multidrug resistance of gastric cancer by integrating metabolic reprogramming with epigenetic regulation. Interventions targeting key components of this modification demonstrate promising therapeutic prospects. However, there is currently a lack of highly specific targeting tools. Future research should focus on deeply deciphering the regulatory networks of lactylation, developing selective inhibitors, and establishing reliable prognostic evaluation models to facilitate clinical translation.