Alpha-Emitter Radium-223 Induces STING-Dependent Pyroptosis to Trigger Robust Antitumor Immunity

  • Small. 2023 Oct 16:e2307448. doi: 10.1002/smll.202307448.
Mengdie Yang  1  2 ,  Haipeng Liu  3 ,  Jingjing Lou  4 ,  Jiajia Zhang  1  2 ,  Changjing Zuo  5 ,  Mengqin Zhu  1  2 ,  Xiaoyi Zhang  1  2 ,  Yuzhen Yin  1  2 ,  Yu Zhang  1  2 ,  Shanshan Qin  1  2 ,  Han Zhang  1  2 ,  Xin Fan  1  2 ,  Yifang Dang  3 ,  Chao Cheng  5 ,  Zhen Cheng  1  6  7 ,  Fei Yu  1  2
Affiliations
  • 1. Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
  • 2. Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, 200072, China.
  • 3. Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
  • 4. Department of Nuclear Medicine, Pudong Medical Center, Fudan University, Shanghai, 201399, China.
  • 5. Department of Nuclear Medicine, the First Affiliated Hospital of Navy Medical University (Changhai Hospital), Shanghai, 200433, China.
  • 6. State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
PMID: 37845027 DOI: 10.1002/smll.202307448
Abstract

Radium-223 (223 Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double-strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering Pyroptosis, an immunogenic cell death. Mechanically, 223 Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent Pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter 223 Ra-induced antitumor immunity, which provides the basis for the development of novel Cancer therapeutic strategies and combinatory therapy.

Keywords
alpha-emitter; immunogenic cell death; pyroptosis; radium-223; stimulator of interferon genes (STING).
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