The incidence and mortality rate of gastric cancer (GC) have remained high worldwide. Although some progress has been made in immunotargeted therapy, the treatment effect remains limited. With more attention has been paid to the immune potential of tumor-associated macrophages (TAMs), but the specific mechanisms of tumor immunity are still unclear. Thus, we screened marker genes in TAMs differentiation (MDMs) through single-cell RNA sequencing, and combined with GC transcriptome data from TCGA and GEO databases, the clinical and TME characteristics, prognostic differences, immune infiltration, and drug sensitivity among different subtypes of patients with GC in different data sets were analyzed. A prognostic model of GC was constructed to evaluate the prognosis and immunotherapy response of patients with GC. In this study, we extensively studied the mutations in MDMs such as CGN, S100A6, and C1QA, and found differences in the infiltration of immune cells and immune checkpoints including M2 TAMs, T cells, CD274, and CTLA4 in different GC subtypes. In the model, we constructed a predictive scoring system with high accuracy and screened out key MDMs-related genes associated with prognosis and M2 TAMs, among which VKORC1 may be involved in GC progression and iron death in tumor cells. Therefore, this study explores the therapeutic strategy of TAMs reprogramming in-depth, providing new ideas for the clinical diagnosis, treatment, and prognosis assessment of GC.
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