The immunoproteasome is a specialized type of proteasome involved in anti-viral adaptive immunity and autoimmunity. Immunoproteasome activation also emerges as part of a broader response to stress. Whether the immunoproteasome is regulated by mitochondrial (mt) or genomic (g) DNA stress, however, is not known. We here demonstrate that cytosolic mtDNA or gDNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon/STAT1 signaling resulting in activation of autoreactive CD8+ T cells. Depletion of the immunoproteasome counteracts mtDNA or gDNA stress-induced cytotoxic CD8+ T cell activation. In patients with idiopathic pulmonary fibrosis, chronic activation of the type I interferon/ immunoproteasome/MHC class I pathway in lung epithelial cells concurs with CD8+ T cell activation. Our data thus unravel DNA stress as an activator of the immunoproteasome and autoreactive CD8+ T cells which represents a novel potential pathomechanism for pulmonary fibrosis and opens new therapeutic perspectives.