Mechanistically, we identify Galectin-9-TIM-3 interaction as a potential pathway driving γδ and MAIT cell depletion in LC.<h4>Conclusion</h4>Our results reveal extensive peripheral immune remodeling in LC-ME/CFS, distinct from idiopathic ME/CFS, and support a model of chronic immune activation and dysregulation. Here, LGALS9 is linked to myalgic encephalomeyelitis/chronic fatigue syndrome.