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Targeting Lysosomal Thiols for Immunogenic Cancer Cell Death

Anton Arkhypov1, Insa Klemt1, Galyna Bila2,3

  • 1Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry II, 91058, Erlangen, Germany.

Angewandte Chemie (International Ed. in English)
|November 4, 2024
PubMed

Insights

A novel therapeutic agent, reversible thiol binder 11, targets cancer cell lysosomes, inducing cell death and potent anti-tumor immunity. This approach shows significant efficacy in preclinical models, offering a promising new avenue for cancer therapy.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Lysosomes (LYs) exhibit altered number and stability in cancer cells, presenting a therapeutic target.
  • Current therapies lack approved drugs that specifically target lysosomes for cancer treatment.

Purpose of the Study:

  • To investigate a novel therapeutic strategy using a reversible thiol binder (compound 11) to target cancer cell lysosomes.
  • To evaluate the efficacy and immune response induced by compound 11 in a preclinical cancer model.

Main Methods:

  • Treatment of cancer cells with compound 11 to induce lysosomal thiol alkylation.
  • Assessment of lysosomal reactive oxygen species (ROS) levels, lysosomal stability, and cancer cell death.
  • Evaluation of therapeutic effects in the murine sarcoma Nemeth-Kellner (NK)/Ly-RB model.
  • Analysis of humoral immune response and neutrophil activity in cured mice.

Main Results:

  • Compound 11 treatment increased lysosomal ROS, leading to destabilization, disruption, and immunogenic cancer cell death.
  • In the NK/Ly-RB model, compound 11 extended median survival from 21 to 85 days and cured 40% of mice.
  • Cured mice developed antibodies against tumor cells and exhibited 100% survival upon re-challenge, indicating acquired immunity.
  • Neutrophils in cured mice demonstrated anti-tumor activity via neutrophil extracellular traps (NETs).

Conclusions:

  • Compound 11 demonstrates direct anti-tumor effects by inducing lysosomal damage and immunogenic cell death.
  • The therapy primes both humoral and neutrophil-mediated immune responses against cancer cells.
  • This lysosome-targeting approach represents a promising strategy for cancer-specific therapy.
Keywords:
CancerElectrophilic DrugImmunogenic Cell DeathIntracellular ThiolLysosome

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