Cell-intrinsic functions of PD-L1 activate autophagy and prevent cytokine-induced apoptosis.

Immune checkpoint inhibitor (ICI) therapy triggers complications that are currently attributed solely to immune activation. We hypothesized that target tissue-specific mechanisms also play a role and studied these mechanisms in thyrocytes. We found that thyroidal PD-L1 acts as a cytoprotective regulator, promoting cell survival during cytokine-induced stress. PD-L1 suppression in thyrocytes amplified interferon-γ-driven stress by aberrantly activating AKT-ERK-mTORC1, inhibiting autophagy, augmenting cellular stress, and triggering apoptosis. In a mouse model of ICI-thyroiditis, anti-PD-L1 treatment triggered immune activation while promoting thyrocyte apoptosis. Mechanistically, in mice, both pharmacologic and genetic down-regulation of thyroidal PD-L1 caused autophagic defects. Our findings reveal a role for PD-L1 in protecting thyroid tissue from cytokine-mediated stress and suggest that anti-PD-L1 tissue toxicity may reflect both an immune-mediated attack and intrinsic cellular vulnerability. Our data provide a broader framework for understanding ICI adverse events and for guiding the development of treatment strategies.