Metabolic Reallocation in the Tumor Microenvironment of Colorectal Cancer at Single-cell Resolution

Metabolic reprogramming of diverse cell types within the tumor microenvironment (TME) is crucial for tumor progression. While previous single-cell studies have identified a set of up- or down-regulated pathways, they often overlook the broader question of how metabolic activity is dynamically allocated among competing processes. Here we present a computational framework integrating multiple single-cell transcriptomic datasets for human colorectal cancer (CRC) to quantify metabolic resource allocation strategies in the TME. Our analysis revealed cell-type-specific metabolic reallocation occurring at both global and local levels and a diverse mode of regulation of metabolic reallocation by novel signaling modules, metabolic reallocation regulators (MRRs), that occur specifically in cancer cells, suggesting a complex network of signaling-metabolism crosstalk during cancer progression. Activities of these MRRs are significantly associated with biological and clinical features of the tumors, highlighting the critical role of metabolic reallocation in cancer progression. By characterizing the metabolic plasticity of the TME and its regulatory drivers, this study advances our understanding of CRC metabolism and offers insights into precision medicine strategies targeting metabolic dependencies.