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Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis

Cellular & Molecular Immunology volume 20, pages 51–64 (2023)Cite this article

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Abstract

Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8+ T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.

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Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the Institute of Systems Medicine, Chinese Academy of Medical Sciences, to verify whether the request is subject to any intellectual property or confidentiality obligations. Any data and materials that can be shared will be released via a material transfer agreement. All raw RNA-sequencing data can be found at the NCBI Sequence Read Archive (accession number: PRJNA818773).

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Funding

YM is supported by the National Science and Technology Innovation 2030 Major Project of China (2022ZD0205700), Natural Science Foundation of China (NSFC, 81972701), CAMS Innovation Fund for Medical Sciences (CIFMS; 2021-I2M-1-074, 2022-I2M-2-004), National Special Support Program for High-level Talents, China Ministry of Science and Technology (National Key Research and Development Program, Grant 2017YFA0506200), and Innovative and Entrepreneurial Team Program (Jiangsu Province).

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Authors and Affiliations

  1. Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 10005, China

    Jinfeng Chen, Ziqi Jin, Shuqing Zhang, Xiao Zhang, Peipei Li, Heng Yang & Yuting Ma

  2. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China

    Jinfeng Chen, Ziqi Jin, Shuqing Zhang, Xiao Zhang, Peipei Li, Heng Yang & Yuting Ma

  3. National Key Laboratory of Medical Immunology, Shanghai, 200433, China

    Heng Yang & Yuting Ma

  4. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China

    Yuting Ma

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Contributions

Study conception and design: YM. Data collection: JC, YM, SZ, ZJ, XZ. Analysis and interpretation of results: JC, YM, PL, HY. Draft manuscript preparation: YM, JC. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Yuting Ma.

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Chen, J., Jin, Z., Zhang, S. et al. Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis. Cell Mol Immunol 20, 51–64 (2023). https://doi.org/10.1038/s41423-022-00956-0

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