JAK inhibitors alleviate EGFR-inhibitor-induced diarrhea by protecting intestinal stem cells from adaptive-immune-exacerbated injury

While intestinal stem cells (ISC) are essential for epithelial homeostasis, their dynamic regulation during immune-mediated injury remains undefined. Here we show that suppression of jejunal ISC proliferation contributes to pathology arising from oral EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) treatment. Suppression of adaptive immunity via genetic intervention reverses ISC suppression and accelerates mucosal repair via inhibiting the TKI-induced, chemokine-directed migration of T and B lymphocytes from Peyer’s patches. Spatial transcriptomics reveals enhanced crosstalk between adaptive immune cells and ISCs in the jejunum. Ex vivo modelling demonstrates that activated T cells directly impair ISC survival through IFN-γ and TNF, with IFN-γ-induced JAK (Janus kinase) /STAT signaling serving as a critical downstream effector. Accordingly, targeted JAK inhibition mitigates EGFRi (epidermal growth factor receptor inhibitor)–induced diarrhea without substantially compromising antitumor efficacy. This work thus redefines TKI-induced enteropathy as an immune-driven pathology and identifies JAK inhibition as a mechanism-based supportive management of targeted therapy toxicities. Immune-related adverse effects often hinder targeted therapies, such as severe diarrhoea caused by EGFR tyrosine kinase inhibitor treatment. Here authors show that EGFR inhibition induces diarrhoea via changes in the jejunal chemokine milieu, facilitating migration of T and B lymphocytes from Peyer’s patches to the jejunum, which results in inhibited intestinal stem cell proliferation via IFN-γ-induced JAK/STAT signalling.