Lenvatinib exacerbates colitis by inhibiting intestinal vascular endothelial MAdCAM-1-mediated B cell trafficking

The use of lenvatinib (Lenv) in advanced hepatocellular carcinoma (HCC) patients is associated with a range of adverse events, including gastrointestinal toxicities, yet the underlying mechanisms remain poorly understood. Here, we demonstrated that Lenv exacerbated both acute and chronic colitis in mouse models by impairing intestinal B cell homeostasis, leading to reduce intestinal B cells and plasma cells, along with decreased IL-10 and IgA secretion. Mechanistically, Lenv decreased MAdCAM-1 expression in intestinal vascular endothelial cells via the VEGFR/PLCγ/PKC/p65 signaling, thereby disrupting B cell homing to the gut. Notably, blockade of either p65 or MAdCAM-1 abrogated Lenv-induced B cell loss and colitis exacerbation. Furthermore, in both tumor-bearing mice and HCC patients receiving Lenv treatment, decreased serum sMAdCAM-1 levels correlated with reduced serum IgA and disruption of intestinal immune homeostasis. Thus, our results show a mechanism for Lenv disrupts intestinal immune homeostasis and implicate serum sMAdCAM-1 may serve as a potential biomarker for monitoring B cell-mediated intestinal immune dysfunction during Lenv therapy.