A single-cell immune cell atlas of trigeminal neuralgia identifies cross-lineage programs linked to carbamazepine resistance

Background Trigeminal neuralgia (TGN) is a disabling neuropathic pain condition. Neurovascular compression of the trigeminal nerve root is the widely accepted cause, yet a proportion of patients derive no lasting benefit from microvascular decompression or pharmacotherapy with carbamazepine (CBZ), suggesting the involvement of additional pathogenic mechanisms. Neuroimmune dysregulation has been increasingly implicated, but the peripheral immune landscape across the full clinical trajectory of TGN—from drug-naïve to treatment-refractory—has not been systematically characterized. Here we constructed a single-cell immune atlas spanning this continuum to identify cell-type-specific programs linked to CBZ response and resistance. Methods Peripheral blood mononuclear cells from 11 donors (healthy controls, untreated TGN, CBZ-responsive, and CBZ-non-responsive patients) were profiled by single-cell RNA sequencing with paired T/B cells receptor sequencing. An intradural trigeminal nerve compression mouse model was used for flow cytometric validation. Analyses included trajectory inference, metabolic pathway scoring, and intercellular communication network modeling. Results Across 122,582 high-quality cells, immune remodeling followed a gradient of severity rather than a simple on/off pattern. Untreated patients showed acute cytotoxic CD8⁺ T cells expansion and pro-inflammatory monocytes activation; these changes partially reverted in CBZ responders. Non-responders, however, exhibited a qualitatively distinct state of cross-lineage functional remodeling: a pro-inflammatory CD8_T_TNF population emerged and expanded, cytotoxic CD8_T_GZMB cells switched from an acute effector program to a sustained NF-κB-centered inflammatory program, regulatory T cells were selectively depleted in association with elevated YBX1, inflammatory B_CD80 cells expanded alongside transitional B_ZBTB16 cells, and monocytes polarized toward a CTNNB1-associated pro-fibrotic and angiogenic phenotype. Intercellular communication analysis identified an “inflammation–matrix remodeling–angiogenesis” signaling pattern enriched in the non-responsive group. Conclusions CBZ treatment resistance in TGN is accompanied by systemic, cross-lineage immune reprogramming into a sustained treatment-non-responsive configuration rather than by quantitative changes in cell abundance alone. The transcriptional checkpoints identified here may offer candidate biomarkers and potential therapeutic targets for refractory TGN.