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ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway

Yuanqin Yang1,2, Meng Wu3, Dongqing Cao1

  • 1Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Science Advances
|October 6, 2021
PubMed

Insights

The ZBP1-MLKL necroptosis pathway in tumor cells is crucial for radiation-induced antitumor immunity. This pathway enhances type I interferon responses and activates the cGAS-STING pathway, improving radiotherapy outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Cell Death

Background:

  • Necroptosis, a regulated form of necrosis, influences tumor progression and the immunogenicity of dying cells.
  • The specific role of intrinsic necroptotic signaling in tumor cells for radiation-induced antitumor immunity is not well understood.

Purpose of the Study:

  • To investigate the contribution of the ZBP1-MLKL necroptotic cascade within tumor cells to radiation-induced antitumor immunity.
  • To elucidate the molecular mechanisms linking necroptosis and STING signaling in response to irradiation.

Main Methods:

  • Analysis of the ZBP1-MLKL necroptotic pathway in irradiated tumor cells.
  • Assessment of type I interferon responses and cytoplasmic DNA accumulation.
  • Investigation of cGAS-STING pathway activation and its interplay with necroptosis.
  • Evaluation of the effects of caspase-8 ablation on STING activation and antitumor responses.

Main Results:

  • The ZBP1-MLKL necroptotic cascade in irradiated tumor cells is essential for mounting an antitumor immune response.
  • ZBP1-dependent MLKL activation promotes type I interferon production post-irradiation.
  • Necroptosis induces cytoplasmic DNA accumulation, which autonomously activates the cGAS-STING pathway, creating a positive feedback loop.
  • Blocking caspase-8 enhances STING activation and radiotherapy's antitumor effects via MLKL activation.

Conclusions:

  • ZBP1-MLKL necroptosis signaling amplifies radiation-induced antitumor immunity through a positive feedback loop with the intrinsic cGAS-STING pathway.
  • Radiotherapy leverages tumor cell necroptosis and STING signaling to bridge cellular damage with robust immune responses.
  • Targeting this necroptosis-STING axis offers a potential strategy to enhance radiotherapy efficacy.

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