CHRNA5 drives pancreatic cancer progression by promoting tumorigenesis and remodeling immune invasion microenvironment via CAMKII/AKT/NF-κB-CCL20 axis

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis, characterized by a distinct tumor microenvironment featuring perineural invasion (PNI), high tumor malignancy, and immune evasion. This study aims to identify the crucial cholinergic receptor involved in PDAC progression and elucidate its underlying mechanisms. Methods Transcriptomic analyses of public PDAC datasets, immunohistochemical staining, and cellular assays were conducted to investigate the enrichment of cholinergic signaling and the tumor-promoting effects of acetylcholine (ACh) in PDAC. We integrated three machine learning models, single-cell RNA-seq reanalysis, in vitro and in vivo experiments to identify alpha5-nicotinic acetylcholine receptor (CHRNA5) as a central mediator of PDAC progression. RNA sequencing and rescue experiments were carried out to elucidate the mechanisms of CHRNA5. Furthermore, KN93, a CaMKII inhibitor, was used to assess the therapeutic potential of targeting CHRNA5-mediated pathways in the PDAC tumor microenvironment. Results Integrated multi-omics analysis, cellular and experimental assays demonstrated the tumor-promoting roles of ACh and CHRNA5, while rescue experiments confirmed that CHRNA5 knockdown abrogated ACh-induced effects. Notably, CHRNA5 inhibition produced more pronounced anti-tumor responses in C57BL/6 mice compared to BALB/c mice. Mechanistically, CHRNA5 shaped an immunosuppressive tumor microenvironment by transcriptionally upregulating CCL20 via CAMKII/AKT/NF-κB signaling, thereby promoting the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Furthermore, the CAMKII inhibitor KN93 effectively suppressed both tumorigenesis and immune evasion. Conclusion Collectively, our findings identify CHRNA5 as a critical driver of PDAC progression by promoting malignant behaviors and reshaping the immune microenvironment, highlighting its potential as a promising therapeutic target in pancreatic cancer.