FISH confirmed stage-specific shifts in macrophage abundances and close spatial interactions between SPP1<sup>+</sup> macrophages and Tc in HCC specimens.<h4>Conclusion</h4>We provided a stage-resolved framework to delineated macrophage heterogeneity during CLDs progression and identified SPP1 and KLF2 as candidate prognostic biomarkers and potential therapeutic targets in HCC. This evidence concerns the gene KLF2 and hepatocellular carcinoma.