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An inducible RIPK3-driven necroptotic system enhances cancer cell–based immunotherapy and ensures safety
Kok-Siong Chen, … , Natalia Claire Mendonca, Khalid Shah
Kok-Siong Chen, … , Natalia Claire Mendonca, Khalid Shah
Published November 19, 2024
Citation Information: J Clin Invest. 2025;135(2):e181143. https://doi.org/10.1172/JCI181143.
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Research Article Immunology Oncology Article has an altmetric score of 18

An inducible RIPK3-driven necroptotic system enhances cancer cell–based immunotherapy and ensures safety

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Abstract

Recent progress in cancer cell–based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible receptor-interacting protein kinase 3–driven (RIPK3-driven) necroptotic system that serves a dual function of safety switch as well as inducer of immunogenic cell death, which in turn stimulates antitumor immune responses. We show that activation of the RIPK3 safety switch triggered immunogenic responses marked by an increased release of ATP and damage-associated molecular patterns (DAMPs). Compared with other existing safety switches, incorporating the RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, the RIPK3 system reinvigorated the TIME by promoting DC maturation, polarizing the macrophages toward a M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of the RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell–based therapy, with broader implications for cellular therapies.

Authors

Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah

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Figure 2

Cell death induced by the RIPK3 safety switch is more immunogenic than the RapaCas9 or HSV-TK system in vitro.

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Cell death induced by the RIPK3 safety switch is more immunogenic than t...
(A) CT2A and CT2A-RIPK3 cell viability assay following treatment with 1 nM B/B for different durations. (B) CT2A and CT2A-RC9TK cell viability assay upon treatment with rapamycin in a dose-dependent manner for 24 hours. (C) CT2A and CT2A-RC9TK cell viability assay following treatment with 25 nM rapamycin for different durations. (D) CT2A and CT2A-RC9TK cell viability assay following treatment with GCV in a dose-dependent manner for 72 hours. (E) CT2A and CT2A-RC9TK cell viability assay upon treatment with 0.1 μg/mL GCV for different durations. (F) Western blot analysis of p-MLKL, p-RIPK3, cleaved caspase 3, and HMGB1 levels following treatment or without B/B in CT2A and CT2A-RIPK3 cells and with or without treatment with rapamycin or GCV in CT2A and CT2A-RC9TK cells, based on the respective EC50 dose and duration. (G) Box plot of ATP release assay following treatment with or without B/B in CT2A and CT2A-RIPK3 cells or treatment with or without rapamycin or GCV in CT2A and CT2A-RC9TK cells, based on the respective EC50 dose and duration.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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