Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer with poor prognosis. Pan-cancer genomic analyses have suggested that polyploidization contributes to cancer progression, by promoting chromosomal instability and malignant evolution. However, its impact on iCCA remains unexplored, partly due to the abundance of stroma and the limited cohort size. This study assessed tumor cell ploidy at the single-cell level via chromosome FISH to examine its association with intratumoral heterogeneity and effects on iCCA pathogenesis. Both iCCA and hepatocellular carcinoma exhibited intratumoral heterogeneity in tumor cell ploidy, with a strong correlation between median ploidy and heterogeneity levels. Polyploid iCCA demonstrated aggressive features including high invasiveness, increased proliferation, and poor differentiation. Tumor cells in polyploid iCCA overexpressed IL6, potentially driving tumor aggressiveness, while suppressing anti-tumor immunity. These findings highlight ploidy alterations as determinants of iCCA pathogenesis and suggest that targeting ploidy could offer a novel approach to precision medicine for iCCA