Lysosomal lipid peroxidation mediates immunogenic cell death

Area of Science:

• Oncology
• Cell Biology
• Immunology

Background:

• Cancer cells utilize lysosomal degradation for nutrient recycling, essential for their growth.
• Hydroxychloroquine is investigated as a lysosomal inhibitor in cancer therapy, but its precise mechanisms of cytotoxicity are not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which lysosomal inhibitors induce tumor cell death.
• To investigate the immunogenic potential of lysosomal-targeted cancer cell death.

Main Methods:

• Utilized DC661, a dimeric chloroquine analog inhibiting palmitoyl-protein thioesterase 1 (PPT1).
• Assessed lysosomal lipid peroxidation, membrane permeabilization, and subsequent cell death.
• Evaluated the immunogenicity of the induced cell death pathway, including T lymphocyte responses.

Main Results:

• DC661 treatment led to lysosomal lipid peroxidation and membrane permeabilization, causing cancer cell death.
• The observed lysosomal cell death pathway triggered intrinsic immunogenicity.
• This immunogenicity promoted the clearance of tumor cells mediated by T lymphocytes.

Conclusions:

• Inhibition of PPT1 by dimeric chloroquine analogs induces cancer cell death via lysosomal damage.
• Lysosomal cell death pathways can elicit anti-tumor immune responses.
• These findings support the combined use of lysosomal inhibitors and immunotherapy in cancer treatment strategies.