Lysosomal lipid peroxidation mediates immunogenic cell death

Abstract

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.

Figure 1. DC661 induces lysosomal lipid peroxidation and immunogenic cell death.

The PPT1 inhibitor DC661 promotes LLP resulting in LMP and immunogenic cell death, marked by cell surface expression of CALR. DC662-mediated LLP can be reversed by NAC, which is transported into lysosomes via the cysteine transporter MFSD12.