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

  • Cell Rep. 2026 Jun 23;45(6):117496. doi: 10.1016/j.celrep.2026.117496.
Shuqi Cai  1 ,  Min-Wei Yang  2 ,  Luju Jiang  3 ,  Zheqi Weng  1 ,  Xin Wang  4 ,  Xueshiyu Ma  2 ,  Yan-Miao Huo  5 ,  Wei Liu  6 ,  Shan Zhang  7 ,  Shu-Heng Jiang  8
Affiliations
  • 1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
  • 3. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 4. Departments of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, No.71, Xinmin Street, Changchun, Jilin 130021, P.R. China.
  • 5. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China. Electronic address: [email protected].
  • 6. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China. Electronic address: [email protected].
  • 7. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: [email protected].
  • 8. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: [email protected].
PMID: 42241282 DOI: 10.1016/j.celrep.2026.117496
Abstract

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.

Keywords
CP: cancer; CP: neuroscience; antitumor immunity; cancer neuroscience; nerve dependence; nerve-cancer interactions; neuroimmunology; pancreatic cancer; perineural invasion; tumor microenvironment.
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