Lysosomal lipid peroxidation mediates immunogenic cell death

• Published in: The Journal of clinical investigation Vol. 133; no. 8
• Main Authors: Phadatare, Pravin, Debnath, Jayanta
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 17-04-2023
• Subjects: Biochemistry; Cancer; Care and treatment; Cell death; Chloroquine - pharmacology; Health aspects; Humans; Hydroxychloroquine; Hydroxychloroquine - metabolism; Immunogenic Cell Death; Lipid Peroxidation; Lysosomes; Lysosomes - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; T cells; United States
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI169240

Cancer cells rely on lysosome-dependent degradation to recycle nutrients that serve their energetic and biosynthetic needs. Despite great interest in repurposing the antimalarial hydroxychloroquine as a lysosomal inhibitor in clinical oncology trials, the mechanisms by which hydroxychloroquine and other lysosomal inhibitors induce tumor-cell cytotoxicity remain unclear. In this issue of the JCI, Bhardwaj et al. demonstrate that DC661, a dimeric form of chloroquine that inhibits palmitoyl-protein thioesterase 1 (PPT1), promoted lysosomal lipid peroxidation, resulting in lysosomal membrane permeabilization and tumor cell death. Remarkably, this lysosomal cell death pathway elicited cell-intrinsic immunogenicity and promoted T lymphocyte-mediated tumor cell clearance. The findings provide the mechanistic foundation for the potential combined use of immunotherapy and lysosomal inhibition in clinical trials.