Background <p>Colitis-associated colorectal cancer (CAC) is driven by chronic inflammation and immune dysregulation. However, how macrophage state heterogeneity is organized across different stages of CAC progression remains unclear.</p> Methods <p>Here, using genetic depletion, single-cell transcriptomics, and pharmacological intervention, and analysis of human colitis-associated colorectal cancer specimens, we identify stage-associated remodeling of CD169-associated macrophage states during CAC progression.</p> Results <p>We demonstrate that CD169 marks functionally distinct macrophage states with opposing roles: CD169-low macrophages predominate during colitis and exhibit pro-inflammatory features, whereas CD169-mid/high macrophages emerge at tumor stages, localize preferentially to para-tumor regions, and display immunosuppressive and immune-inert interaction profiles. These observations support stage-associated remodeling of CD169-associated macrophage states during CAC progression. Importantly, CD169 depletion restrains tumor growth and enhances intratumoral T cell infiltration, highlighting CD169-associated macrophages as potential therapeutic targets in inflammation-driven colorectal tumorigenesis.</p> Conclusions <p>Together, our findings reveal stage-associated remodeling of CD169-associated macrophage states during CAC progression, with distinct CD169 states exhibiting divergent immune regulatory features at different disease stages. These findings highlight the importance of considering macrophage state heterogeneity when targeting CD169-associated pathways and support further investigation of state-informed therapeutic strategies in inflammation-driven colorectal tumorigenesis.</p>