FADS1-mediated Efferocytosis in Tumor-Associated Macrophages Shapes an Immunosuppressive Microenvironment in Gastric Cancer

Abstract

Tumor-associated macrophages (TAMs) play a central role in tumor progression and therapeutic resistance. Alterations in unsaturated fatty acids (UFAs) metabolism are known to contribute to the immunosuppressive properties of TAMs. However, the complex regulatory relationship between UFAs metabolism and TAMs during gastric cancer (GC) progression remains largely unclear. Through a comprehensive analysis of single-cell RNA sequencing and transcriptomic data, we found that the UFAs biosynthesis-related enzyme FADS1 holds prognostic significance in GC within TAMs. Clinically, a high infiltration of FADS1+TAMs strongly correlates with poor prognosis and immunotherapy resistance across several GC cohorts. Using in vitro co-culture systems and in vivo mouse models, our data suggest that FADS1+TAMs actively contribute to an immunosuppressive microenvironment, potentially driving CD8+T cell dysfunction. Mechanistically, our findings indicate that FADS1 mediated DHA synthesis and activated PPARγ, which subsequently promotes efferocytosis and inhibit the STING-IFN-I signaling pathway in TAMs. Notably, systemic pharmacological targeting of FADS1 exerted a significant sensitizing effect in mouse ectopic GC models, inhibiting tumor growth, enhancing CD8+T cells cytotoxicity, and improving the efficacy of PD-1 blockade. Overall, our study highlights FADS1+TAMs as a critical component of GC progression and a potential exploratory biomarker for immunotherapy responsiveness. Furthermore, pharmacological inhibition of FADS1 represents a promising combinatorial strategy for reshaping the TME and enhancing immune checkpoint blockade efficacy in preclinical settings.