Xbp1-driven lipid metabolism promotes immunosuppression in lung cancer: Jianpi Chutan Jiedu formula reshapes metabolic-immune crosstalk.

[BACKGROUND] Lung cancer (LC) is the primary cause of cancer-related mortality. The Jianpi Chutan Jiedu Formula (JCJ) is an improved formula developed in clinical practice; its mechanism of action in treating LC remains unclear.

[PURPOSE] To examine the antitumor efficacy and provide insight into the fundamental mechanisms of JCJ in LC.

[METHODS] The expression of X-box binding protein 1 (XBP1) was identified through bioinformatics analysis combined with a tissue microarray. LLC, H1975, and A549 cells stably overexpressing Xbp1 gene were established via lentiviral infection. Lipidomic profiling and lipid content determination were used to analyze the effects of Xbp1 on LC cells and lipid metabolism. The effects of LLC cells overexpressing Xbp1 on DC2.4 cells were investigated by coculture. In vivo therapeutic effects and chemical composition of JCJ were evaluated. The antitumor effects and mechanisms of JCJ on Xbp1-overexpressing LLC cells were evaluated using flow cytometry, multiplex immunohistochemistry, and multifactorial detection.

[RESULTS] XBP1 protein is highly expressed in LC. Xbp1 overexpression led to marked lipid accumulation in LLC, H1975, and A549 cells. Xbp1 enhanced lipid metabolism in LLC cells, resulting in TME immunosuppression. LLC cells overexpressing Xbp1 inhibited DC2.4 activation and weakened antigen presentation function in coculture systems. The chemical composition of JCJ was analyzed, and 29 blood-permeable components were identified. JCJ exhibited potent antiproliferative effects, significantly inhibiting the tumor growth regulated by Xbp1. Additional analysis revealed that JCJ alleviated lipid-induced TME immunosuppression and enhanced the antitumor immunity of dendritic cells and T cells. JCJ exerts the described effects by inhibiting the IRE1α/XBP1 pathway.

[CONCLUSION] JCJ modulates lipid metabolism and reshapes the immunosuppressive tumor microenvironment by regulating the IRE1α/XBP1 pathway, thereby improving dendritic cell and T cell function. The inhibitory effect of JCJ highlights the potential of herbal medicine as an adjunct therapeutic strategy for LC treatment.