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

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 5

Tumor cell death induced by the RIPK3 safety switch synergistically improves the antitumor therapeutic benefits of cancer cell–based therapy and elicits long-term immunity in vivo.

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Tumor cell death induced by the RIPK3 safety switch synergistically impr...
(A) Schematic of the experimental timeline for intracranial GBM implantation, the cCT2A–IFN-β–RIPK3 treatment schedule, and activation of the RIPK3 suicide system via B/B administration. (B) Representative images and graph of Fluc signal in C57BL6 mice following intracranial implantation of WT CT2A cells and intratumoral treatment with cCT2A–IFN-β–RIPK3 with (n = 5) or without (n = 5) B/B administration. (C) Kaplan-Meier curves demonstrating the survival probability of C57BL6 mice after intracranial implantation of WT CT2A cells and intratumoral treatment with cCT2A–IFN-β–RIPK3 with (n = 5) or without (n = 5) B/B administration. (D) Representative images and graph of Fluc signal after intracranial implantation with WT CT2A cells into the contralateral brain hemisphere of the surviving C57BL6 mice from C (n = 3) and naive mice (n = 3). (E) Kaplan-Meier curves demonstrating the survival probability of the surviving C57BL6 mice from C and naive mice after rechallenge with WT CT2A cells. (F) Representative images and graph of Fluc signal in C57BL6 mice after intracranial implantation of WT Gl261 cells and intratumoral treatment with cGL261–IFN-β–RIPK3 with (n = 7) or without (n = 5) B/B administration. (G) Kaplan-Meier curves demonstrating the survival probability of the C57BL6 mice after intracranial implantation of WT Gl261 cells and intratumoral treatment with cGL261–IFN-β–RIPK3 with (n = 7) or without (n = 5) B/B administration. (H) Representative images and graph of Fluc signal after intracranial implantation with WT GL261 cells into the contralateral brain hemisphere of the surviving C57BL6 mice from G (n = 3) and naive mice (n = 5). (I) Kaplan-Meier curves demonstrating the survival probability of the surviving C57BL6 mice from G and naive mice after rechallenge with WT GL261 cells. All data were assessed by log-rank (Mantel-Cox) test with Bonferroni correction and represent the mean ± SEM (C, E, G, and I).