Lysosomal lipid peroxidation mediates immunogenic cell death

by Selleckchem | Aug 28 2023

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.

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The study conducted by Bhardwaj et al., published in the Journal of Clinical Investigation (JCI), focuses on understanding the mechanisms by which lysosomal inhibitors, such as hydroxychloroquine and DC661, induce cytotoxicity in tumor cells and their potential implications for cancer treatment.

Cancer cells have a high demand for nutrients to support their growth and proliferation. They rely on lysosome-dependent degradation to recycle nutrients for their energetic and biosynthetic needs. Lysosomes are cellular organelles responsible for breaking down various biomolecules, including proteins and lipids, through the action of hydrolytic enzymes.

Hydroxychloroquine, an antimalarial drug, has been of great interest in clinical oncology trials for its potential to inhibit lysosomal function. However, the specific mechanisms by which hydroxychloroquine and other lysosomal inhibitors induce cytotoxicity in tumor cells have remained unclear.

In this study, Bhardwaj et al. investigated the effects of DC661, a dimeric form of chloroquine that inhibits palmitoyl-protein thioesterase 1 (PPT1), on tumor cells. PPT1 is an enzyme involved in the removal of palmitate groups from proteins, and its inhibition can disrupt cellular processes.

The researchers found that DC661 promoted lysosomal lipid peroxidation, which led to lysosomal membrane permeabilization. This disruption of lysosomal integrity resulted in tumor cell death. Importantly, this lysosomal cell death pathway triggered cell-intrinsic immunogenicity, meaning that it stimulated an immune response within the dying tumor cells.

Furthermore, the study demonstrated that the lysosomal cell death pathway induced by DC661 facilitated T lymphocyte-mediated tumor cell clearance. This suggests that combining immunotherapy, which harnesses the immune system to target cancer cells, with lysosomal inhibition could be a promising approach for cancer treatment.

The findings of this study provide a mechanistic understanding of how lysosomal inhibitors, specifically DC661, induce cytotoxicity in tumor cells. The study also highlights the potential of combining immunotherapy with lysosomal inhibition as a therapeutic strategy in clinical trials. This research may contribute to the development of novel treatment approaches for cancer.