Lysosomal lipid peroxidation regulates tumor immunity

Area of Science:

• Cell Biology
• Immunology
• Biochemistry

Background:

• Palmitoyl-protein thioesterase 1 (PPT1) inhibitors can cause cell death, but the precise mechanism remains unclear.
• Standard programmed cell death pathways are not implicated in PPT1 inhibitor-induced cytotoxicity.

Purpose of the Study:

• To elucidate the mechanism of cell death induced by PPT1 inhibition.
• To investigate the immunogenic properties of PPT1 inhibitor-treated cells and their potential in cancer therapy.

Main Methods:

• Utilized PPT1 inhibitors (e.g., DC661) in cell culture and mouse models.
• Assessed cell death pathways, lysosomal function, lipid peroxidation, and immune responses.
• Investigated the role of the lysosomal cysteine transporter MFSD12 and the antioxidant N-acetylcysteine (NAC).

Main Results:

• PPT1 inhibition triggers lysosomal lipid peroxidation (LLP), leading to lysosomal membrane permeabilization and cell death.
• Cell death is rescued by NAC, highlighting the role of oxidative stress, and requires the lysosomal transporter MFSD12.
• PPT1 inhibition induces cell-intrinsic immunogenicity, enhancing T cell-mediated anti-tumor responses in vivo, particularly in "immune hot" tumors.

Conclusions:

• Lysosomal lipid peroxidation drives a unique form of immunogenic cell death.
• PPT1 inhibition represents a promising strategy for enhancing cancer immunotherapy, especially when combined with antioxidants like NAC.