Pi Ji Pills reshape the pancreatic cancer immune microenvironment and enhance the efficacy of gemcitabine through dual mechanisms of PI3K/AKT pathway blockade and NETs inhibition

ETHNOPHARMACOLOGICAL RELEVANCE: Pancreatic cancer presents a significant challenge in clinical treatment. Pi Ji Pills (PJP) is a compound formula made up of seven traditional Chinese medicinal herbs. It has demonstrated positive clinical outcomes in the treatment of pancreatic cancer, and its potential pharmacological mechanisms warrant further investigation. AIM OF THE STUDY: This study aimed to identify the possible mechanisms by which PJP inhibits pancreatic cancer, followed by experimental verification and more profound exploration. MATERIALS AND METHODS: An in vivo pancreatic cancer xenograft model was established to observe the effect and safety of PJP on tumor growth. The SW1990 cells were cultured to investigate the intervention effects of PJP-containing serum on the malignant biological behavior of pancreatic cancer cells. Subsequently, network pharmacology analysis was employed to explore the potential mechanisms. Furthermore, both in vivo and in vitro experiments were conducted to validate the core pathways and targets. An in-depth exploration was performed, with a focus on the role of neutrophil extracellular traps (NETs) in the inhibition of pancreatic cancer by PJP. RESULTS: PJP inhibits tumor growth, and its combination with gemcitabine exhibits enhanced inhibitory effects, partially alleviating immune suppression. PJP-containing serum was found to inhibit the malignant biological behavior of SW1990 cells. naringenin, atractylenolide I, isoalantolactone, curcumenol, parthenolide, and arglabin are the main active components of PJP. PJP inhibits PI3K/AKT pathway, key to its anti-pancreatic cancer effects. Additionally, PJP's treatment inhibited SW1990 cell proliferation indenpence of reducing IL-8 and downregulating NETs-related protein expression in the co-culture system. CONCLUSIONS: PJP combats pancreatic cancer and enhances gemcitabine efficacy by remodeling the immunosuppressive tumor microenvironment. This anticancer effect may be attributed to a dual-target mechanism involving suppression of the PI3K/AKT pathway and regulation of NETs formation in the tumor microenvironment.