Novel Lysosomal‐Associated Transmembrane Protein 4B‐Positive Stem‐Like Cell Subpopulation Characterizes High‐Risk Colorectal Cancer Subtypes

ABSTRACT Colorectal cancer (CRC) exhibits substantial intertumoral heterogeneity, largely attributable to multiple tumor stem‐like cell populations, whose molecular identities and clinical significance remain incompletely defined. This study delineates tumor‐intrinsic stem‐like cell diversity and its prognostic implications through single‐cell transcriptomic profiling of 171,906 tumor epithelial cells ( n = 152), integrated with bulk transcriptomic ( n = 1389) and genomic ( n = 1077) datasets. Functional validation was conducted via in vitro assays and multiplex immunofluorescence. A previously unrecognized lysosome‐associated transmembrane protein 4B‐positive (LAPTM4B + ) stem‐like cell cluster was identified, distinct from the classical leucine‐rich repeat‐containing G‐protein coupled receptor 5‐positive (LGR5 + ) population. LAPTM4B + cells exhibited MYC pathway activation and 8q chromosomal gains, with preferential enrichment in microsatellite‐stable, POLE wild‐type, and left‐sided tumors. Stratification based on LAPTM4B + /LGR5 + stem‐like cell ratios defined four CRC stem‐like subtypes (CSS), with CSS2 (LAPTM4B + ‐dominant) associated with the poorest prognosis (HR = 2.31, p < 0.001). The combined expression of LAPTM4B and LGR5 demonstrated superior predictive power for CRC progression compared to either marker alone (AUC = 0.820 vs. 0.715/0.699), underscoring the synergistic influence of distinct stem‐like cell populations on patient outcomes. These findings provide novel insights into CRC heterogeneity and cooperative interactions among diverse stem‐like populations shaping disease outcomes.