A Study on the Regulation of PD-L1 Immune Escape by Gastric Cancer CAF Subsets Based on Metabolic Heterogeneity through Lactation Modification
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Keywords
cancer-associated fibroblasts, metabolic heterogeneity, lactation modification, PD-L1, immune escape
Abstract
High-glycolytic iCAFs in the gastric cancer tumor microenvironment exhibit significant metabolic heterogeneity and can secrete large amounts of lactate through the reverse Warburg effect, thus constructing an immunosuppressive microenvironment. Lactic acid is transported into tumor cells via MCT1 and regulates PD-L1 expression through a dual mechanism: AARS1-mediated histone lactation can upregulate PD-L1 transcription, while HAT1-catalyzed lactation at PD-L1 sites can block ubiquitination degradation and maintain protein stability. Highly expressed PD-L1 binds to PD-1 on CD8⁺T cells and inhibits T cell killing function, mediating immune escape and immune resistance in gastric cancer. Targeting lactate metabolism and lactation modification can effectively reverse drug resistance and has synergistic therapeutic value with immunosuppressants. Currently, this field still suffers from shortcomings such as insufficient mechanistic evidence, a lack of gastric cancer-specific research, and limitations in detection technology.
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