New direction: identification of immunoinflammatory subtypes and potential therapeutic targets for cholangiocarcinoma.

Background: Cholangiocarcinoma (CHOL) is a rare cancer with low survival rates. Despite advances in precision medicine targeting molecular subtypes, the immune subtypes of CHOL remain poorly understood. This study aimed to identify immune subtypes of CHOL and investigate their implications in the metabolic regulation of macrophage functions in inflammation.

Methods: We conducted a comprehensive analysis of transcriptome and single-cell sequencing data from multiple databases to classify the immune subtypes of CHOL. Immune cell infiltration within the tumor microenvironment (TME) and the metabolic pathways involved in macrophage activation and polarization were also analyzed.

Results: Two distinct immune subtypes, immune-infiltrated CS1 and immune-depleted CS2, were identified in CHOL. CS1 exhibited a highly active TME with substantial immune cell infiltration, including macrophages, and activation of immune-related signaling pathways, such as inflammatory and interferon pathways. In contrast, CS2 was characterized by a deficiency in immune components and poorer prognosis. Metabolic regulation of macrophages, particularly the downregulation of oxidative phosphorylation in CS1, suggested a shift towards glycolysis as an energy source for activated macrophages, contributing to the immune-responsive phenotype observed in CS1. Additionally, the oncogenic role of DLX5 in CHOL was revealed, with potential impacts on macrophage functions in inflammation.

Conclusion: This study provides insights into immune subtype classification, novel biomarker identification, and the metabolic regulation of macrophage functions in CHOL. Understanding macrophage metabolic reprogramming within immune subtypes may contribute to the development of targeted immunotherapies for CHOL.