An antibiotic that mediates immune destruction of senescent cancer cells
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).
Authors
- Xuezhao Feng
- René Bernards (ORCID: https://orcid.org/0000-0001-8677-3423)
- Nicole N. van der Wel (ORCID: https://orcid.org/0000-0001-6392-3417)
- Jian Zheng (ORCID: https://orcid.org/0000-0001-9831-7038)
- Roderick L. Beijersbergen (ORCID: https://orcid.org/0000-0003-0116-4130)
- Onno B. Bleijerveld (ORCID: https://orcid.org/0000-0002-9395-2347)
- Liesbeth Hoekman (ORCID: https://orcid.org/0000-0002-3552-6390)
- Cor Lieftink (ORCID: https://orcid.org/0000-0002-2754-4150)
- Jian Chen (ORCID: https://orcid.org/0009-0002-2472-6626)
- Liqin Wang (ORCID: https://orcid.org/0000-0002-9881-6432)
- Jing Wang (ORCID: https://orcid.org/0000-0003-4896-0142)
- Shuang Deng (ORCID: https://orcid.org/0009-0009-4025-0788)
- Gabriele Casagrande Raffi
- Marit Steur
- Chuting Zeng
- Feng Wang
- Jinzhe Mo
- Zhen Chen (ORCID: https://orcid.org/0009-0007-7842-5446)
Institutions
- Sun Yat-sen University (CN)
- The Netherlands Cancer Institute (NL)
- Oncode Institute (NL)
- Sun Yat-sen University Cancer Center (CN)
- University of Amsterdam (NL)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1073/pnas.2417724121
- Citations
- 8
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- Mark Foundation For Cancer Research
- National Natural Science Foundation of China
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Natural Science Foundation of China-Guangdong Joint Fund
- Basic and Applied Basic Research Foundation of Guangdong Province
- HORIZON EUROPE European Research Council