An Endothelial Address for the Sphingosine 1-Phosphate Axis: Cell-Type Attribution of 171 Sphingolipid Targets Across 27 Human Cancers

Sphingolipid enzymes have been nominated as cancer targets for three decades. Six pathway genes are the target of an approved drug, with every approval being for multiple sclerosis, ulcerative colitis, or a lysosomal storage disease, and none for cancer. We defined a cell-type attribution index (CTAI) placing each gene on an axis from the malignant compartment to the microenvironment, computed it from compartment means in pan-cancer tumour single-cell data, reproduced it in proteomic and spatial data, and crossed it with cell-line dependency. CTAI reproduces at Spearman +0.30 against the protein index and +0.50 against the spatial one. S1PR1 and SPNS2 rank endothelium first in 23 of 31 and 22 of 31 datasets. Normal tissue immune fraction declines as CTAI rises (ρ = −0.52 core set, −0.60 genome-wide). Modelability, the proportion of genes yielding a dependency model that meets the predictability criterion, falls across the four functional groups (Cochran–Armitage p = 0.0024). Matched control genes fall the same way (p = 7.9 × 10−7), indicating that the gradient is not specific to sphingolipids. Clinical-stage targets sit in the low-attribution, low-dependency quadrant of our set, but genome-wide, with the target development level and literature volume held constant, that quadrant carries no advantage (odds ratio 1.05, 95% confidence interval 0.89 to 1.24). Attribution splits this pathway into a cell-autonomous arm, which cell-line dependency screens measure directly, and a sphingosine 1-phosphate arm expressed mostly outside the malignant compartment, in cells those screens do not contain.