Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma
Menée à l'aide de modèles cellulaires de cholangiocarcinome intrahépatique, de l'analyse de cellules immunitaires à l'aide de la cytométrie en flux à haute dimension et de l'analyse transcriptomique spatiale d'échantillons tumoraux, cette étude examine les modifications moléculaires et cellulaires liées à l'expression d'interleukine IL-6 par les cellules cancéreuses
Background : High serum levels of interleukin 6 (IL-6) predict poor prognosis in intrahepatic cholangiocarcinoma (iCCA), a malignancy that often develops in a chronically inflamed milieu. Here, tumour cells are capable of autonomously producing and engaging autocrine IL-6 signalling, yet the consequences of this remain unknown.
Objective : This study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.
Design : We generated CRISPR-activated IL-6high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.
Results : Chronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.
Conclusions : These findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.
Gut , article en libre accès, 2026