Gastric premalignant lesions can develop into cancer through multiple steps and inflammation plays a critical role. The aim of this study is to uncover the characteristics of macrophages and their gene expression in premalignant gastric lesions to identify novel biomarkers and potential targets for treatment. We used the computational algorithm CIBERSORT to estimate immune cell subsets present in gastric tissue. We applied WGCNA to identify inflammation-related modules and hub genes. Single-cell analysis was used to identify macrophage sub-clusters specific to pathology. In addition, the in-vitro experiment was performed to verify the mechanism of the key inflammatory factors in the growth of gastric cancer. WGCNA identified a module that was positively correlated with pathological changes and highly related to inflammation scores. Single-cell analysis revealed a macrophage subset, and we observed that S100A8 and S100A9 + macrophages made up a significantly higher proportion in early gastric cancer (EGC) tissues. Our functional enrichment analysis suggested that these macrophages may play a role in gastric tumorigenesis through the activation of the NFκB signaling pathway. In vitro experiments verified that S100A9 can promote the proliferation and migration of AGS cells through the TLR4-NFκB signaling pathway, and the S100A8/S100A9 inhibitor Paquinimod can inhibit their proliferation and migration. Our findings suggest that S100A8 and S100A9 + macrophages may activate the TLR4-NFκB signaling pathway to promote cell proliferation and migration leading to gastric tumor progression. Macrophages with high expression of S100A8/S100A9 are critical in the progression of gastric inflammation to cancer. Cytokine S100A9 can activate the TLR4-NFκB signaling pathway and promote the proliferation and migration of gastric adenocarcinoma cells.