Targeting Lysosomal Thiols for Immunogenic Cancer Cell Death

The number and stability of lysosomes (LYs) are different in cancer and healthy cells that makes them a possible target for cancer specific therapy. However, no LY‐targeting drug is clinically approved yet. We describe in this paper a new therapeutic approach based on alkylation of lysosomal thiols in cancer cells by reversible thiol binder 11. The treatment with 11 increases the level of lysosomal reactive oxygen species leading to their destabilization, disruption and immunogenic cancer cell death. These effects are not observed in healthy cells. In murine sarcoma Nemeth‐Kellner (NK)/Ly‐RB model, 11 exhibits the spectacular therapeutic effect: it extends the lifespan of the treated mice from 21 to 85 days and cures 40% of mice. The survived mice develop antibodies against tumor NK/Ly‐RB cells. Their repeated challenge with the NK/Ly‐RB cells results in 100% mice survival compared to 0% survival in the control group of naïve mice. Ex vivo data indicate that neutrophils in spleen of the cured animals are also involved in targeting cancer cells and produce neutrophil extracellular traps. In summary, 11 induces the direct antitumor effect supported by humoral immune responses, as well as priming neutrophil’s reaction against tumors.