Tumor microenvironment heterogeneity and progression mechanisms in intrahepatic cholangiocarcinoma: A study based on...

Intrahepatic cholangiocarcinoma (ICC) is characterized by high malignancy, and its global incidence is predicted to continue to increase over the past decades. However, the mechanisms underlying ICC pathogenesis and progression remain unclear.

The training cohort consisted of single-cell sequencing of 12 treatment-naive ICC samples and spatial transcriptomics of 4 ICC samples. The validation cohort consisted of RNA-seq data from 87 ICC tumor samples. Finally, we validated our findings via multiplex immunofluorescence, organoids, and mouse models both in vivo and in vitro. We found significant heterogeneity within the tumor microenvironment of patients with ICC. ICC cells were classified into 5 molecular subtypes, and we revealed that aspartate beta-hydroxylase (ASPH) was a marker gene for invasion subtypes. We then selected cepharanthine as an ASPH inhibitor that effectively suppressed tumor progression. Regarding the ICC lymphatic metastasis mechanism, we found that tumor cells in N1 lymph nodes highly expressed tumor-specific major histocompatibility complex II molecules but lacked costimulatory factors CD80/CD86, inducing a state of anergy in CD4+ T cells, which might facilitate ICC immune evasion.

The tumor microenvironment of ICC was heterogeneous. ASPH markedly enhanced ICC invasion. The ASPH inhibitor cepharanthine significantly inhibits ICC progression and may serve as a targeted therapeutic drug for ICC. Tumor cells in N1 lymph nodes demonstrate high expression of tumor-specific major histocompatibility complex II molecules, but silencing of costimulatory factors such as CD80/CD86 induces CD4+ T cells into an anergic state. Our study indicated that ASPH and major histocompatibility complex II may serve as novel therapeutic targets for ICC.