Double trouble for LCH lesions. Sengal et al perform a detailed phenotypic and functional analysis of the inflammatory infiltrate in LCH lesions. Confirming and extending prior observations, Sengal et al show that the constitutively active MAPK LCH cells are a minority of the population, whereas exhausted CD4 and CD8 T cells, regulatory T cells, and myeloid-derived suppressor cells predominate. Using a BRAFV600E^CD11C preclinical model of systemic LCH, they demonstrate that α-PD-1 and MEKi have synergistic activity in reducing the size of the LCH lesions.