Mode of action of the 3 FDA-approved cGVHD therapies. Ibrutinib inhibits BTK, which mediates signal transduction downstream from the BCR including PLCγ2 activation and thereby blocks activation of B cells. Ibrutinib also blocks ITK, which contributes to proximal TCR signaling, activating PLCγ1, which then activates nuclear factor of activated T-cells, nuclear factor κB, and MAPK pathways, ultimately leading to T-cell activation, cytokine release, and proliferation. Belumosudil (KD025) inhibits rho-associated ROCK2, which is downstream of cytokine and growth factor receptors and integrins. ROCK2 activation promotes the production of the proinflammatory cytokines IL-21 and IL-17, inhibits Tregs, and promotes fibrosis. Ruxolitinib inhibits JAK1 and 2. JAK1 and 2 mediate downstream effects of multiple cytokines such as IL-6, IFN-γ, and common γ chain cytokine receptors. Reduced STAT1 and STAT3 activation on ruxolitinib treatment results in increased Treg numbers and lower levels of collagen deposition.