ObjectiveThe diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment (‘STIM’ classification).DesignWe applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease.ResultsiCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, namedimmune classical(~10%) andinflammatory stroma(~25%), differ in oncogenic pathways and extent of desmoplasia, with theinflammatory stromashowing T cell exhaustion, abundant stroma andKRASmutations (p<0.001). Analysis of cell–cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, thedesert-like class(~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas thehepatic stem-likeclass (~35%) is enriched in ‘M2-like’ macrophages, mutations inIDH1/2andBAP1,andFGFR2fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between aKRAS/p19murine model and theinflammatory stromaclass (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises aKRAS-mutant iCCA murine model to anti-PD1 therapy.ConclusionsWe describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.