The mechanism by which specific tumor subsets in colorectal cancer (CRC) use alternative metabolic pathways, particularly those modulated by hypoxia and fructose, to alter the tumor microenvironment (TME) remains unclear. This study aimed to identify these malignant subpopulations and characterize their intercellular signaling networks and spatial organization through an integrative multi-omics approach.

Leveraging bulk datasets, single-cell RNA sequencing, and integrative spatial transcriptomics, we developed a prognostic model based on hypoxia-and fructose metabolism-related genes (HFGs) to delineate tumor cell subpopulations and their intercellular signaling networks.

We identified a specific subset of stanniocalcin-2 positive (STC2+) malignant cells spatially enriched within tumor regions and strongly associated with poor prognosis. This subset served as a key signaling hub in the TME, exhibiting increased epithelial–mesenchymal transition activity. STC2+ cells engage in two spatially organized ligand–receptor interactions: the growth differentiation factor 15 (GDF15)—transforming growth factor beta receptor 2 (TGFBR2) pathway targeting endothelial cells and the migration inhibitory factor (MIF)—(cluster of differentiation 74 [CD74]+C-X-C motif chemokine receptor 4 [CXCR4]) pathway targeting macrophages.

This study identified a malignant cell state in CRC that is metabolically defined and spatially limited, including liver metastases, and is characterized by elevated STC2 expression and active immune-stromal interactions. Given the interplay between metabolic reprogramming and TME remodeling, STC2+ malignant cells are a functionally significant subpopulation and a potential therapeutic target.