The combination of flaxseed lignans and PD-1/ PD-L1 inhibitor inhibits breast cancer growth via modulating gut microbiome and host immunity

• DOI: 10.1016/j.drup.2025.101222
• Publication Date: 2025-02-28T16:32:33Z
• Authors: Hao Wu; Jiena Liu; Xing-Hua Zhang; Shengye Jin; Ping Li; Huidi Liu; Liuying Zhao; Jianyu Wang; Shilu Zhao; Hong-Da Tian; Jin-Ru Lai; Yi Hao; Gui-Rong Liu; Kaijian Hou; Meisi Yan; Shu-Lin Liu; Da Pang

Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed investigate inhibitory effects flaxseed lignans (FL) on biological behaviors BC and evaluate roles FL in enhancing anticancer PDi. HPLC was used detect content enterolactone (ENL), bacterial transformation product FL. Transcript sequencing performed identified CD38 as a downstream target gene ENL. CD38-overexpressing cells were constructed cell proliferation, colony formation, wound healing transwell assays assess function ENL/CD38 axis vitro. Multiplexed immunohistochemistry (mIHC) CyTOF changes tumor immune microenvironment (TIM). 16S rDNA explore gut microbiota mice. A series vivo experiments conducted mechanisms converted ENL by administration inhibited progression malignant downregulating CD38, key associated immunosuppression blockade resistance. The mIHC assay revealed that enhanced CD3+, CD4+ CD8+ reduced F4/80+ TIM. confirmed regulatory combination PDi (FLcPDi) In addition, analysis demonstrated FLcPDi treatment significantly elevated abundance Akkermansia and, importantly, response mice treated antibiotics. FL/ENL/CD38 progression. modulating host immunity.