EACR26-0950

A senolytic ADC drives synthetic lethality and immune surveillance for senescent cancer cell destruction

J. Chen¹, Y. Deng¹, G. Casagrande Raffi², X. Feng¹, S. Lu¹, H. Xie¹, R. Beijersbergen², J. Yang¹, R. Bernards², L. Wang¹

¹Sun Yat-sen University Cancer Center, Department of Experimental Research, Guangzhou, China
²The Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, Netherlands

Introduction:

Senolytics, drugs that selectively eliminate senescent cells, exhibit potent efficacy when combined with pro-senescence cancer therapies.

Material and method:

Using CRISPR/Cas9-based genetic screens across diverse senescent cancer cell models, we identified cFLIP (an extrinsic apoptosis inhibitor) and SLC25A23 (a mitochondrial calcium transporter) as common vulnerabilities exploitable for targeted elimination.

Result and discussion:

To recapitulate the biological effects of suppressing both genes, we engineered a senolytic antibody-drug conjugate (ADC) pairing the DR5-agonist antibody conatumumab with salinomycin, an antibiotic that disrupts mitochondrial homeostasis. This ADC unleashes synergistically extrinsic apoptosis in senescent tumor cells via salinomycin-driven JNK activation, which amplifies DR5 expression in a potent feedback loop. Strikingly, it also induces immunogenic cell death, characterized by pyroptosis and IL-18 release, thereby recruiting cytotoxic T and NK cells to bolster antitumor immunity.

Conclusion:

Our study pioneers a "synergy-immune stimulating ADC" (siADC) framework that fuses apoptosis induction with pyroptotic immune activation, showing a potent senolytic efficacy in multiple animal models, combining with independent pro-senescence regimens that underscore a high translational viability.

Acknowledgement:

Jian Chen, Gabriele Casagrande Raffi, Rene Bernards, and Liqin Wang are named inventors on a patent application based on the study. Rene Bernards and Liqin Wang are shareholders of Oncosence. The other authors declare no competing interests. We thank members of the Wang, Bernards, and Beijersbergen laboratories for helpful discussion and insightful feedback. This work was supported by the European Research Council as ERC-787925; 19-051-ASP from the Mark Foundation; ASP-II grant-Bernards 2023; KWF-12539 from the Dutch Cancer Society; LSH-TKI-LSHM20083 from Health Holland; and KWF lnfrastructure lnitiatives ScreeninC 12539. 2024ZD0525004 from the National Health Commission of the PRC-Noncommunicable Chronic Diseases-National Science and Technology Major Project; 2024YFA0918403 from the National Key Research and Development Program of China; W2432050, W2421020, 82521103 and 82372695 from the National Natural Science Foundation of China; 2023ZT10Y094 from Guangdong Pearl River Talent Program.