Single-cell and spatial transcriptomics reveal lactate-active epithelial-immune cell crosstalk that reprograms the...

The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeutic resistance. Integrating single-cell transcriptomics, spatial transcriptomics, and bulk sequencing datasets, this research delineated the lactate metabolic landscape across colorectal cancer (CRC) tumor ecosystems. Single-cell profiling revealed significant metabolic activity in both the epithelial and myeloid compartments. Consequently, a lactate metabolism score (LMscore) was developed, which is based on four core genes (COX15, SLC25A13, COX10, MPC1). An elevated LMscore has been demonstrated to reprogram epithelial developmental trajectories and reconfigure intercellular communication networks, notably through EFNA1-EPHA3-mediated crosstalk with fibroblasts and endothelial cells. Spatial transcriptomics corroborated intimate spatial colocalization and metabolic pathway co-enrichment between lactate-active epithelia and fibroblasts. Clinically, high LMscore independently predicts a decreased overall survival across multiple cohorts and defines a "cold" tumor immune phenotype. This phenotype is characterized by an accumulation of immunosuppressive cells including M2 macrophages and cancer-associated fibroblasts (CAFs) and a reduction in effector T-cell infiltration. This ultimately results in a refractory response to immune checkpoint blockade. Mechanistically, COX15 emerges as a central regulator of lactate metabolic dysregulation, coinciding with fibroblast-derived TGF-β secretion and immunosuppressive niche formation. Functional validation confirms that COX15 targeting suppresses tumor proliferation. This work establishes LMscore as a clinically robust biomarker for prognostication and immunotherapy response prediction, thereby providing a mechanistic foundation for metabolic reprogramming-targeted combinatorial therapies in CRC.