Lysosomal lipid peroxidation mediates immunogenic cell death

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 o...

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Bibliographic Details
Published in:The Journal of clinical investigation 2023-04, Vol.133 (8)
Main Authors: Phadatare, Pravin, Debnath, Jayanta
Format: Article
Language:English
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
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI169240