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Tumor-associated macrophages (TAMs) are pivotal immunosuppressive components of the tumor microenvironment (TME) in gastric cancer (GC), yet their heterogeneity and metabolic crosstalk with tumor cells remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 75,743 cells from 11 GC tissues and identified four distinct TAM subsets (TAM-APOE, TAM-IDO1, TAM-SKAP1, TAM-POLB), each exhibiting unique functional signatures. Among these, the TAM-APOE subset, enriched in lipid metabolism and complement pathways, showed the strongest interaction with tumor cells via the MIF-CD74 axis. Functional studies revealed that GC-derived MIF promotes TAM-APOE polarization, upregulating immunosuppressive genes and enhancing tumor progression. In vivo, MIF overexpression in GC cells increases subcutaneous tumor volume, while MIF knockdown decreases tumor weight. Crucially, Milatuzumab, a CD74-targeting antibody, reversed MIF-induced TAM immunosuppression in vitro. Our research provides a comprehensive map of GC-TAM heterogeneity; reveals that the MIF-CD74 axis is a key driver of TAM-mediated immune suppression; and proposes that CD74 blockade is a new therapeutic strategy for GC.