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Background Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with rising global incidence. Neural invasion (NI) occurs in up to 70% of ICC patients and is recognized as an independent predictor of poor prognosis. However, the cellular architecture and molecular interactions within and surrounding tumor-associated nerves remain poorly understood. Herein, we aimed to systematically dissect the tumor-neural microenvironment and investigate the crosstalk between malignant cells, Schwann cells, immune cells, and cancer-associated fibroblasts (CAFs) in ICC.Methods Tumor tissues and clinical data from ICC patients were analyzed using single-cell RNA sequencing (scRNA-seq), spatial-enhanced-resolution-omics-sequencing (Stereo-seq) and multiplex immunohistochemistry to characterize cellular phenotypes and spatial organization. The biological roles and mechanisms of Schwann cells and CAFs in ICC were determined using the in vitro co-culture system and in vivo mouse models.Results Clinically, neural invasion was significantly associated with poor survival in ICC patients. Integrated scRNA-seq and Stereo-seq analyses revealed distinct cellular compositions and spatial architectures associated with NI status. Basal-like malignant subpopulations and inflammatory CAFs (iCAFs) were preferentially enriched in the perineural niche of NI-positive tumors. Basal-like tumor cells exhibited activation of nerve-related signaling programs, including axon guidance and nerve development. Among stromal populations, iCAFs displayed the highest neural interaction potential and recruited Schwann cells via the IGF1-IGF1R axis, thereby promoting Schwann cell proliferation and invasion. Notably, Schwann cells in the NI microenvironment engaged extensive interactions with CD8+GZMK+ effector memory T cells, driving a stressed and exhausted state accompanied by impaired cytotoxic activity. This Schwann cell-mediated T cell dysfunction contributed to an immunosuppressive niche that facilitated tumor progression. Importantly, pharmacological inhibition of IGF1R significantly reversed the immunosuppressive microenvironment and suppressed tumor growth in the orthotopic model.Conclusions Basal-like malignant cells orchestrate CAFs and Schwann cells reprogramming to establish an immunosuppressive tumor-neural niche that promotes ICC progression. Targeting cancer-immune-neural interactions represents a promising therapeutic strategy for ICC.