FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma.

Tumor-associated macrophages (TAMs) play a critical role in promoting tumor progression and represent a promising target for immunotherapeutic intervention. However, the phenotypic characteristics and polarization dynamics of TAMs remain poorly understood, largely due to the complex cellular heterogeneity within the tumor microenvironment. In this study, we comprehensively characterize the heterogeneity of TAMs in gastric adenocarcinoma (GA), with a particular focus on immunosuppressive subsets. Our findings demonstrate that TAMs undergo multidirectional differentiation and exhibit diverse immunoregulatory functions. Among them, FPR3⁺ macrophages are identified as a distinct immunosuppressive population associated with poor patient prognosis. Functional assays using shRNA-mediated knockdown and specific agonists reveal that FPR3 regulates macrophage proliferation and polarization and is essential for TAM formation and maintenance. Mechanistically, FPR3 upregulates FZD7 and CCDC88C, leading to activation of the intracellular Wnt/PCP pathway and downstream JNK signaling, thereby promoting TAM development. Collectively, our study identifies FPR3 as a novel marker of immunosuppressive TAMs, elucidates its mechanistic role in macrophage plasticity, and offers new insights into potential therapeutic strategies for targeting the tumor microenvironment in GA.