巴马汀通过抑制HOXA10-STAT3轴调节肿瘤微环境并改善吉西他滨在PDAC中的疗效

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a five-yearsurvival below 12%. This poor prognosis stems from the late diagnosis, intrinsicchemoresistance, immunosuppression, and a dense desmoplastic stroma that promotes tumorprogression and therapeutic resistance. Current first-line treatments, including gemcitabine/nab-paclitaxel and FOLFIRINOX, are limited due to patient-specific responses, highlighting the needfor broadly effective therapies. Our previous work identified palmatine, a naturally occurringisoquinoline alkaloid, as a potent inhibitor of pancreatic stellate cells (PSCs) and PDAC cellgrowth. In this study, we evaluated the therapeutic efficacy of palmatine in combination withgemcitabine using an orthotopic KPC syngeneic mouse model. Combination treatmentsignificantly reduced tumor volume compared to vehicle or gemcitabine alone. Spatial immuneprofiling and transcriptomics of excised tumors revealed that combination treatment wasassociated with marked reduction in macrophage density, whereas gemcitabine alone displayedclear presence of macrophage-enriched immune neighborhoods not distinctly observed in thecombination group. Additionally, gemcitabine treated tissues exhibited a higher frequency ofneutrophil and dendritic cell-rich aggregates. Notably, the predominant immunemicroenvironment in combination-treated samples demonstrated a reduction in dendritic cellpopulations, alongside modest increases in CD4⁺ and CD8⁺ T cell subsets. Integration of bulkRNA-sequencing and spatial transcriptomics identified elevated Hoxa10 expression andactivation of the IL-6/STAT3 signaling axis in mesenchymal cells. CyTOF analysesdemonstrated increased HOXA10, phosphorylated STAT3, and epithelial-mesenchymaltransition (EMT)-associated proteins in PSCs co-cultured with PANC-1 cells, which wereattenuated by combination treatment. Functional assays, including colony formation, confirmedthat combination therapy was more effective in suppressing clonogenic growth than gemcitabinealone. ChIP-seq data with HOXA10 pull-down from ENCODE project identified STAT3 as apotential HOXA10 target. These findings suggest that palmatine enhances gemcitabine efficacyby mitigating the immunosuppressive tumor microenvironment by targeting the HOXA10-STAT3 axis, and disrupting EMT programs. This combination represents a promising strategy toovercome PDAC chemoresistance and improve therapeutic outcomes. Supported in part throughZachry Endowment and VA Merit Award BX003876 (APK).