Single-cell and spatial transcriptomics in intrahepatic cholangiocarcinoma: spatial immune ecosystems, metabolic remodeling, and immunotherapeutic implications

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy characterized by pronounced cellular, spatial, and metabolic heterogeneity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) are beginning to resolve this complexity by linking malignant, immune, stromal, and metabolic states to their tissue context. This review synthesizes recent single-cell and spatial studies of iCCA across four spatial contexts: adaptive immune regions containing tertiary lymphoid structures (TLSs), barriers formed by stromal and myeloid cells at the invasive front, myeloid niches shaped by hypoxia, and metastatic ecosystems involving immune and stromal cells. These niches connect tumor heterogeneity with immune regulation, stromal remodeling, metabolic adaptation, and therapeutic vulnerability. We also evaluate how crosstalk between metabolism and immunity shapes macrophage polarization, T-cell dysfunction, and treatment response, while distinguishing computationally inferred interactions from functionally supported mechanisms. The field is therefore moving from cataloging additional cell states and spatial niches toward establishing which ecosystem features are reproducible across cohorts, mechanistically supported, clinically measurable, and informative for treatment response. Current evidence supports a view of iCCA as a spatially organized and metabolically regulated tumor ecosystem that can guide biomarker development and rational immunotherapeutic strategies.