Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

ILC1-like cells via autocrine TGF-β. We assess cancer patient-derived public datasets and reveal the presence of IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells within the tumor microenvironment and associate IL-35 with poor prognosis. Collectively, our findings identify and implicate IL-35 as a key driver of NK cell plasticity, promoting the acquisition of features associated with tissue residency and weakened effector functions, and could be relevant in pathophysiological contexts, highlighting IL-35 as an attractive target for future immunotherapies aimed at enhancing NK cell clinical activity.