Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer

Abstract Colorectal cancer (CRC) is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. Here, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular crosstalk during CRC development. Additionally, we created a CRC sc-eQTL map identifying 16,833 significant pairs across 28 cell subtypes, with over 76% of sc-eQTLs being cell-type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score (PRS) derived from sc-eQTLs substantially improved CRC risk prediction. We prioritized rs4794979 that is associated with an increased CRC risk (OR=1.11, P=2.04×10-12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts (CAFs), simultaneously induces CD8+ T cells exhaustion via LGALS9-TIM3 axis, thereby facilitating CRC development. Blocking LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit CRC progression.