<p>Colon cancer remains a major cause of global cancer mortality, characterized by complex interactions between genetic, epigenetic, and immune factors. This study investigates the prognostic value of efferocytosis-related genes and their role in colon cancer progression and immune modulation. A prognostic signature relied on efferocytosis-related genes was developed using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Immune infiltration, immune checkpoint expression, and tumor microenvironment characteristics were analyzed using single-sample gene set enrichment analysis (ssGSEA), ESTIMATE, and tumor immunophenotype (TIP) frameworks. S1PR5 was knocked down in SW1116 and SW620 cells. The effect of S1PR5 on colon cancer growth and macrophage regulation in vivo and in vitro. Colon cancer patients were stratified into high- and low-risk groups, with high-risk patients demonstrating significantly worse survival outcomes. S1PR5, a key gene in the model, was markedly overexpressed in colon cancer tumors and correlated with advanced clinical stages, poor survival outcomes, and diminished responses to immunotherapy. Furthermore, S1PR5 knockdown could inhibit colon cancer cell activity and increase macrophage polarization from M0 to M1. Our research developed an efferocytosis-related gene prognostic model and identified S1PR5 as a key biomarker. S1PR5 showed significant associations with advanced clinical stages, immunosuppressive microenvironments, and unfavorable survival outcomes, underscoring its potential as both a prognostic marker and a therapeutic target in colon cancer.</p>