Spatial blueprint of colorectal cancer identifies Hypoxic CAF program that orchestrates Go-or-Grow decisions and predicts outcomes.

The tumor microenvironment (TME) critically influences colorectal cancer (CRC) progression, but its spatial organization and functional impact remain incompletely understood. We integrated single-cell transcriptomics (412,208 cells) with spatial transcriptomics (76,627 spots from 38 sections of 32 patients) to deconstruct the CRC microenvironment, employing computational approaches for niche identification, SCENIC network inference, and cell-cell communication analysis. Key findings were validated in primary CAF cultures, Seahorse metabolic analysis, and the TCGA cohort. We identified nine microenvironmental niches, including a co-localized "pro-tumorigenic triad" (desmoplastic stromal, angiogenic inflammatory, and TAM-dominant suppressive niches), creating an integrated ecosystem supporting tumor growth. We discovered a Hypoxic CAF subtype associated with a spatial "Go-or-Grow" switch in tumor cells-proximity to Hypoxic CAFs inversely correlated with proliferation but positively with invasion and metabolic stress programs. HMGA2 was identified as a key transcriptional regulator of this CAF state, which was significantly associated with adverse clinical outcomes in univariate survival analysis. In vitro co-culture experiments showed that these CAFs suppress proliferation while enhancing invasion through metabolic reprogramming from oxidative phosphorylation to glycolysis. Our study reveals spatially co-localized niches forming a "pro-tumorigenic triad" and identifies HMGA2-regulated Hypoxic CAFs associated with metabolic-driven phenotypic switching as candidate therapeutic targets for spatially informed CRC intervention.