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<p>Interleukin (IL)-18 functions primarily through its 18-kDa mature form produced from caspase-1 cleavage. However, IL-18 can also be processed by other proteases, leading to the generation of different fragments with less recognized functions. Here, we discover that, in cancer cells, caspase-3 cleavage of IL-18 generates a 15-kDa form of IL-18, referred to as short IL-18. Unlike mature IL-18, short IL-18 is not secreted, and does not bind IL-18Rα; instead, it translocates into the nucleus, facilitating STAT1 phosphorylation at Ser<sup>727</sup> via CDK8, and enhancing the expression and secretion of ISG15. This signaling cascade in cancer cells mobilizes natural killer cells with increased cytotoxicity to eliminate various syngeneic tumors and colitis-associated colorectal cancer in mice. Moreover, patients with colorectal cancer who have an abundance of short IL-18 in the nucleus have a better prognosis. This work highlights a distinct anti-tumor pathway driven by short IL-18.</p>

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Short IL-18 generated by caspase-3 cleavage mobilizes NK cells to suppress tumor growth

  • 期刊论文

  • 发表日期：

    2025年1月31日

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  • Junchen Shen,
  • Yu Zhang,
  • Wenbo Tang,
  • Mingxia Yang,
  • Tong Cheng,
  • Yihui Chen,
  • Shi Yu,
  • Qiuhong Guo,
  • Limin Cao,
  • Xun Wang,
  • Hui Xiao,
  • Lanfeng Wang,
  • Chengyuan Wang,
  • Chen-Ying Liu,
  • Guangxun Meng

摘要

Interleukin (IL)-18 functions primarily through its 18-kDa mature form produced from caspase-1 cleavage. However, IL-18 can also be processed by other proteases, leading to the generation of different fragments with less recognized functions. Here, we discover that, in cancer cells, caspase-3 cleavage of IL-18 generates a 15-kDa form of IL-18, referred to as short IL-18. Unlike mature IL-18, short IL-18 is not secreted, and does not bind IL-18Rα; instead, it translocates into the nucleus, facilitating STAT1 phosphorylation at Ser727 via CDK8, and enhancing the expression and secretion of ISG15. This signaling cascade in cancer cells mobilizes natural killer cells with increased cytotoxicity to eliminate various syngeneic tumors and colitis-associated colorectal cancer in mice. Moreover, patients with colorectal cancer who have an abundance of short IL-18 in the nucleus have a better prognosis. This work highlights a distinct anti-tumor pathway driven by short IL-18.