Abstract Cholinergic signalling, traditionally attributed to the parasympathetic nervous system, is increasingly recognized as an immunoregulatory pathway in diverse disease contexts. Acetylcholine, the primary neurotransmitter in cholinergic signalling, is reported to be secreted by immune cells and plays an important role in hepatocellular carcinoma, liver regeneration, and metabolic dysfunction-associated steatohepatitis. However, whether immune cell-derived ACh influences cancer metastasis to the liver remains unknown. Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, providing a relevant model to interrogate the neuroimmune mechanisms that shape the metastatic microenvironment. Using a spontaneous liver metastasis model generated by orthotopic or splenic injection of murine pancreatic cancer cells, we observed a marked induction of the ACh-synthesizing enzyme choline acetyltransferase (ChAT) in immune cells during liver metastatic progression, suggesting that immune cells contribute to a local immune-derived cholinergic niche. These findings identify a previously unrecognized cholinergic-immune axis in the pancreatic cancer metastatic niche, where immune-derived ACh increases during liver metastasis. Targeting neuroimmune pathways may offer new strategies to modulate the liver metastatic microenvironment in PDAC. Citation Format: Xiaotong Long, Christine Chio, Tak W. Mak. Characterize the role of cholinergic signalling in pancreatic cancer liver metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6223.
Long et al. (Fri,) studied this question.
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