Colorectal cancer liver metastases (CRCLM) display distinct histopathological growth patterns (HGPs), with the replacement (RHGP) and encapsulated (EHGP) patterns linked to markedly different prognoses. Despite their clinical relevance, the underlying microenvironmental dynamics shaping these growth patterns remain incompletely understood.

We applied in situ sequencing (ISS) to spatially resolve the transcriptomic landscape of CRCLM tissues, focusing on the tumor–liver interface in RHGP and EHGP lesions. Cellular populations were identified through unsupervised clustering and annotated based on spatial context and marker expression profiles. All patients provided their informed written consent to participate in the tissue biobank of Region Västerbotten, Sweden.

Our analysis revealed distinct populations of inflamed hepatocytes enriched in RHGP lesions, displaying reduced hepatocyte identity and signs of inflammatory reprogramming. These cells were predominantly located at the tumor-liver interface and may be co-opted by tumor-derived signals to promote progression. In contrast, EHGP lesions were characterized by the presence of well-differentiated, non-inflamed hepatocytes. EHGP lesions also showed spatial enrichment of interferon-stimulated gene expression in stromal and tumor cell populations, supporting immune cell recruitment and activation. Furthermore, fibrotic capsules in EHGP lesions exhibited a zonated structure, with the tumor-facing side influenced by tumor-derived signals and the liver-facing side displaying features of hepatic stellate cell activation and immune involvement. This supports a dynamic, immune–fibrotic niche at the tumor border that may restrict invasion.

Our findings reveal distinct microenvironmental programs associated with RHGP and EHGP in CRCLM, suggesting divergent mechanisms of tumor-host interaction with potential relevance for patient stratification and therapeutic intervention.