Spatial Transcriptomics Reveals Stromal-Partitioned Growth in Primary Colorectal Cancer and Host-Permeated Architecture in Liver Metastases

The spatial organisation of the tumour microenvironment plays a central role in shaping immune engagement and tumour progression, yet how spatial principles differ between primary colorectal cancer and metastatic disease remains incompletely defined. Spatial transcriptomics (10x Visium) was integrated with cell-type deconvolution and transcriptional pathway enrichment to characterise tumour, stromal, vascular, and immune architecture across primary colorectal tumours (CRC) and colorectal liver metastases (CRLM). Across primary CRC sections, spatial organisation resolved into compartmentalised architectures in which hyper-proliferative tumour regions enriched for E2F and MYC signalling were segregated from immune-reactive compartments by cancer associated fibroblast (CAF) enriched stromal interfaces. These stromal regions were transcriptionally active, exhibiting enrichment of epithelial–mesenchymal transition, coagulation, and vascular programmes. Cytotoxic immune activity was heterogeneous and spatially constrained, localising to discrete tumour-associated niches or peripheral inflammatory zones rather than uniformly penetrating proliferative tumour cores. In contrast, liver metastases displayed diffuse, host-permeated architectures in which tumour programmes were embedded within resident hepatic immune and vascular frameworks. Metastatic growth was characterised by infiltrative expansion accompanied by strong myeloid and regulatory immune signatures, alongside spatially ordered transitions from stromal–vascular programmes into proliferative tumour states within a highly reactive hepatic environment. Together, these findings demonstrate that primary and metastatic colorectal cancer are governed by distinct spatial organisational principles. While primary CRC frequently exhibits stromal-partitioned, exclusion-prone architectures, liver metastases are shaped by infiltrative growth within a tolerogenic and highly reactive host context. This context-dependent spatial biology underscores the need for spatially tailored therapeutic strategies, targeting stromal architecture in primary tumours versus immune tolerance in metastatic disease.