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

While intestinal stem cells (ISCs) are essential for epithelial homeostasis, their dynamic regulation during immune-mediated injury remains undefined. Jejunal intestinal stem cell (ISC) proliferative suppression emerges as a pathological hallmark of oral EGFR tyrosine kinase inhibitors (TKIs), propelling chemokine-directed migration of T/B lymphocytes from Peyers patches. Genetic ablation of adaptive immunity reversed ISC suppression and accelerated mucosal repair. Spatial transcriptomics revealed enhanced ISC-adaptive immune cell crosstalk in the jejunum.Ex vivo modeling demonstrated activated T cells directly impair ISC survival through IFN-Gamma and TNF-Alpha, with JAK/STAT signaling constituting the critical downstream effector. Targeted JAK inhibition prevented T/B cell-mediated pathology while exhibiting dual efficacy: mitigating EGFRi-induced diarrhea without substantially compromising antitumor efficacy. This work redefines TKI-induced enteropathy as an immune-driven pathology and identifies JAK inhibition as the first mechanism-based supportive therapy, establishing a paradigm for precision management of targeted therapy toxicities.