Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCC), known for its rarity, challenging diagnosis, and bleak prognosis, was subject to a comprehensive exploration of its molecular classification to pave the way for precision medicine approaches. This investigation identified three clinically supported subtypes, namely stem-like, poorly immunogenic, and metabolism. Notably, NCT-501, an inhibitor of aldehyde dehydrogenase 1 family member A1 (ALDH1A1), displayed synergistic effects with nanoparticle albumin-bound–paclitaxel in an organoid model tailored to the stem-like subtype. Dysregulations in oncometabolites were linked to distinct clinical outcomes in both the stem-like and metabolism subtypes, whereas the poorly immunogenic subtype showed a lack of T-cell tumor infiltration. The integrated multiomics analysis not only reaffirmed the existence of these three subtypes but also unveiled underlying heterogeneity in iCC. This extensive proteogenomic investigation provided insights that transcend conventional genomic analysis, allowing for a deeper understanding of the functional consequences of genomic alterations. These findings hold promise for better patient stratification and the development of more rational therapeutic strategies in the realm of iCC.