Macrophage-Specific Loss of Stearoyl-CoA Desaturase 1 Promotes Colon Cancer by Enhancing M2 TAM Polarization

Abstract

In colon cancer (CC), the polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype plays a critical role in immune therapy resistance, yet the underlying metabolic “switch” has not been fully elucidated. While the function of stearoyl-CoA desaturase 1 (Scd1) in tumor cells has been reported, its role in TAMs remains unknown. We generated Lyz2-Cre-driven myeloid-specific Scd1 knockout (Scd1 cKO) mice and wild-type (Scd1 WT) control mice. Both groups were subcutaneously injected with MC38 cells to establish a colon cancer model. Flow cytometry was utilized to assess the polarization status of TAMs and the infiltration of CD8+ T cells in tumor tissues. RNA sequencing (RNA-seq) combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify differentially expressed genes and key signaling pathways. RT-qPCR and Western blot analysis were used to examine the expression of core molecules within these pathways. Scd1 cKO mice exhibited faster tumor growth and increased tumor weight compared to Scd1 WT mice. Scd1 deletion enhanced TAM polarization toward the M2 phenotype and suppressed the Hippo-YAP pathway, leading to CD8+ T cell exhaustion. Furthermore, TT-10 treatment reversed M2 polarization, restored CD8+ T cell infiltration and effector function, and slowed tumor progression. In conclusion, Scd1 knockout in macrophages accelerates colon cancer by promoting M2 polarization via inhibition of the Hippo-YAP pathway, impairing CD8+ T cell function. Targeting the Scd1-Hippo-YAP signaling axis may offer a promising new approach for immunotherapy in colon cancer.