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<p>The STING pathway plays a central role in immune activation; however, STING protein levels decline during the progression of various cancers, including lung cancer, thereby limiting the efficacy of immunotherapies. Our study uncovers a previously unrecognized mechanism whereby ISGylation stabilizes STING by preventing its autophagic degradation, thereby enhancing its immunostimulatory function. Moreover, we demonstrate USP18 as a negative regulator that removes ISGylation from STING, and identify Tanshinone IIA sulfonate (TST) as a potent USP18 inhibitor that enhances STING ISGylation and stabilizes STING protein levels. When combined with the STING agonist diABZi, TST exhibits a synergistic effect, eliciting a potent antitumor immune response by increased infiltration of NK1.1⁺ cells and pronounced suppression of tumor growth in lung cancer models. These findings underscore the therapeutic potential of targeting STING ISGylation, particularly in patients with low STING expression who often respond poorly to current STING-targeted therapies.</p>

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ISGylation prevents autophagic degradation of STING and promotes antitumor immunity in lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月27日

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  • Dan Cao,
  • Bin Huang,
  • Xinming Fu,
  • Ming Liu,
  • Xiaogang Niu,
  • Hongbin Zhai,
  • Hao Huang

摘要

The STING pathway plays a central role in immune activation; however, STING protein levels decline during the progression of various cancers, including lung cancer, thereby limiting the efficacy of immunotherapies. Our study uncovers a previously unrecognized mechanism whereby ISGylation stabilizes STING by preventing its autophagic degradation, thereby enhancing its immunostimulatory function. Moreover, we demonstrate USP18 as a negative regulator that removes ISGylation from STING, and identify Tanshinone IIA sulfonate (TST) as a potent USP18 inhibitor that enhances STING ISGylation and stabilizes STING protein levels. When combined with the STING agonist diABZi, TST exhibits a synergistic effect, eliciting a potent antitumor immune response by increased infiltration of NK1.1⁺ cells and pronounced suppression of tumor growth in lung cancer models. These findings underscore the therapeutic potential of targeting STING ISGylation, particularly in patients with low STING expression who often respond poorly to current STING-targeted therapies.