Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis.

Mitochondrial Lon is a chaperone protein whose upregulation increases the production of mitochondrial reactive oxygen species (ROS). However, there is a lack of information in detail on how mitochondrial Lon regulates cancer metastasis through ROS production in the tumor microenvironment (TME). Our results show that elevated Lon promotes epithelial-mesenchymal transition (EMT) via ROS-dependent p38 and NF-κB-signaling. We further identified pyrroline-5-carboxylate reductase 1 (PYCR1) as a client of chaperone Lon, which induces mitochondrial ROS and EMT by Lon. Mitochondrial Lon induces ROS-dependent production of inflammatory cytokines, such as TGF-β, IL-6, IL-13, and VEGF-A, which consequently activates EMT, angiogenesis, and M2 macrophage polarization. In addition, Lon expression is induced upon the activation and M2 polarization of macrophages, which further promotes M2 macrophages to enhance the immunosuppressive microenvironment and metastatic behaviors in the TME. This raises the possibility that manipulation of the mitochondrial redox balance in the TME may serve as a therapeutic strategy to improve T cell function in cancer immunotherapy.