Nerve-proximal tertiary lymphoid structures predict chemotherapy sensitivity in pancreatic cancer

Summary The complex interplay between nerves, immunity, and tumor progression remains poorly understood, particularly in the context of chemotherapy. Here, we investigated how neural remodeling influences tertiary lymphoid structures (TLSs) and clinical outcomes following neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC). Using tissue samples from 86 treatment-naïve and 49 NAT-treated patients with PDAC, we demonstrated that chemotherapy significantly increases both nerve density (ND) and TLS abundance. Notably, nerve-proximal TLSs (N-TLSs) displayed more mature phenotypes and correlated positively with tumor regression. Spatial transcriptomics of nerve regions showed chemotherapy-induced transcriptional reprogramming of Schwann cells, marked by altered myelination programs and elevated pro-inflammatory signaling. The Schwann cell state shift coincides with TLS accumulation, maturation, and enhanced peri-neural immune infiltration. Collectively, our study indicates a spatially organized neuro-immune axis linking neural remodeling to TLS abundance and maturation after chemotherapy and nominates N-TLS abundance as a potential histological biomarker of treatment response in resected PDAC.