The mutualistic relationship between M2c macrophages of TGFβ1 induction and gastric cancer cells: the correlation between protective mechanisms in the tumor microenvironment and polarization of subtypes of cells

<b>Background:</b> Gastric cancer (GC) is one of the most common malignant tumors worldwide, with fast metastasis and high mortality rate. GC cells and tumor immune microenvironment exhibit high heterogeneity. Multiple pieces of evidence suggest that TGFβ1 intervenes in the tumor microenvironment, immune cells and GC prognosis. The aim of this study is to comprehensively investigate the functional intervention of macrophage polarization subtypes on gastric cancer cell lines in the GC tumor microenvironment, providing valuable insights into tumor microenvironment research and potential targets for treatment strategies. <b>Methods:</b> TCGA database and multiple GEO datasets were used to validate the role of TGFβ1 in cancer prognosis, immune infiltration and subtype macrophage polarization. Construct different subtypes of macrophages and establish cell co culture systems using Transwell chambers. Enzyme linked immunosorbent assay (ELISA), western blotting (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to verify the changes in the metastatic function and defense mechanism of gastric cancer cells (Hgc27 and MKN45) in different co culture systems. Further analyze the effect of gastric cancer cell metabolites on macrophage subtype polarization. <b>Results:</b> TGFβ1 was highly expressed in GC tissues, highly expressed TGFβ1 could reduce the survival time of GC patients. The GC immune infiltration results confirmed the correlation between TGFβ1 and M2 macrophages. The GEO dataset results of gastric cancer at different stages showed that some M2 macrophage markers showed consistent changes with TGFβ1. The WB, ELISA and RT-qPCR have identified TGFβ1-induced polarization of M2c macrophages, most biomarkers are associated with M2c. M2c macrophages can enhance cell migration and function, can inhibit ferroptosis in gastric cancer cells, endowing them with stronger special environmental resistance. Gastric cancer cells tend to polarize towards M2 macrophages, with M2c being the main M2 subtype of macrophages. <b>Conclusion:</b> In conclusion, our study reveals a mutually beneficial symbiotic relationship between M2c macrophages and cancer cells in the microenvironment of gastric cancer tumors. TGFβ1 promotes the production of M2c macrophages, which enhance the function and ferroptosis resistance of gastric cancer cells. Gastric cancer cells provide the material basis for M2c macrophage polarization. This new evidence may provide new insights into developing more effective targeted therapies for gastric cancer to combat the formation of immune escape and metastasis in gastric cancer.