Gut microbiota dysbiosis-associated succinate accumulation is linked to gastric cancer progression and macrophage-related tumour microenvironment remodelling

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Gastric cancer (GC) is a lethal gastrointestinal malignancy regulated by genetic alterations and tumour microenvironment (TME) remodelling. Gut microbiota metabolites can regulate tumour progression through the microbiota–metabolite–immune axis. However, the relationship among GC-associated gut microbiota dysbiosis, succinate accumulation, and macrophage-related immune features remains unclear. This study aimed to investigate whether GC-associated gut microbiota dysbiosis is linked to succinate accumulation and to elucidate the role of succinate in tumour progression and immune microenvironment remodelling. We screened for GC-related and succinate-related microbes using the Peryton and GutMGene databases. Faecal 16S rRNA sequencing and untargeted metabolomics were performed on tumour-bearing and control mice. Network-based target analysis was used to identify potential succinate-related signalling pathways in GC. The effects of succinate on GC cell proliferation, colony formation, migration/invasion, apoptosis, and tumour growth were evaluated using in vitro experiments and a subcutaneous tumour-bearing model. Public single-cell RNA sequencing (scRNA-seq) data were analysed to characterise the GC immune microenvironment, macrophage subset distribution, and CXC chemokine receptor 4 (CXCR4) expression. Bone marrow-derived macrophages (BMDMs) were used to verify the regulatory effects of succinate on CXCR4 expression. GC was associated with significant gut microbiota remodelling and increased faecal succinate levels. Succinate promotes GC cell proliferation, colony formation, migration/invasion, cell survival, and in vivo tumour growth. Multiplex cytokine and chemokine assays revealed upregulated CXCL12 and downregulated CXCL10 levels in succinate-treated tumour tissues. Network analysis revealed that succinate-related targets were enriched in metabolic reprogramming, hypoxic responses, inflammatory immune regulation, and hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor signalling pathways. scRNA-seq analysis indicated enhanced immune-stromal infiltration, intensified intercellular communication, expansion of SPP1⁺ macrophages, and CXCR4-high features in macrophages within GC tissues. In vitro experiments confirmed that succinate upregulated CXCR4 mRNA expression in BMDMs. These findings suggest that GC-bearing status is associated with gut microbiota dysbiosis and faecal succinate accumulation, and that succinate may contribute to malignant phenotypes and CXCL12/CXCR4-related macrophage features in vitro and in a subcutaneous tumour model. However, the current data do not directly demonstrate that microbiota-derived succinate reaches the native gastric tumour microenvironment or that CXCL12/CXCR4-dependent macrophage remodelling is required for tumour growth. Further blocking, rescue, and orthotopic or spontaneous gastric cancer model studies are needed to validate this candidate mechanism in the native gastric tumour microenvironment.

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