Pyruvate partitioning defines an immunosuppressive metabolic niche in colorectal cancer
Purpose. Colorectal cancer (CRC) reprograms glucose metabolism, diverting pyruvate from mitochondrial oxidation toward lactate export. How this partitioning decision is organized across cell types and tissue space, and how it relates to immune programmes, remains unresolved. Methods. We defined a Pyruvate Partitioning Index (PPI) as the difference between an oxidative arm (MPC1, MPC2, PDHA1, PDHB, DLAT, DLD, PDHX) and an export arm (LDHA, LDHB, SLC16A1, SLC16A3, SLC16A7), and computed it across TCGA COADREAD (n = 592), GSE39582 (n = 579), two single-cell atlases (370,115 and 63,689 cells), 13 Visium sections and an exploratory urothelial immunotherapy cohort (IMvigor210, n = 298). Results. PPI was lowest in microsatellite-unstable (MSI) tumours (Mann-Whitney p = 3.8 x 10^-9) and inversely associated with overall survival (log-rank p = 1.2 x 10^-4). Epithelial cells were the most oxidative compartment (median +0.058) and myeloid cells the most export-prone (-0.171; Kruskal p [~] 0), reproduced independently; MMRd epithelium was intrinsically export-shifted (-0.012 vs +0.076 vs +0.192 for MMRd, MMRp and normal). Spatially, PPI was non-random (Moran's I significant in 12/13 sections), with low-PPI spots enriched for SPP1+ macrophages, myofibroblasts and plasma cells, but not CD8+ T-cell factors. Low-PPI tumours showed coordinated increases in immune-checkpoint, myeloid and Treg programmes (checkpoint rho = -0.262), and network perturbation identified LDHA as the hub. Conclusions. Pyruvate partitioning is cellularly and spatially organized in CRC and defines a myeloid-stromal immunosuppressive niche. Because MSI tumours (the best CRC immunotherapy responders) had the lowest PPI, the PPI-response relationship appears cancer-type specific and requires validation in CRC cohorts.