IDDF2026-ABS-0187 Crosstalk between schwann cells and iCAF Shapes an immunosuppressive microenvironment in intrahepatic cholangiocarcinoma

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.