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<p>Immunosuppressive metabolites are major drivers of tumor immune suppression. Among these, kynurenine (Kyn) is produced through the catalysis of tryptophan (Trp) 2,3-dioxygenase (TDO) in hepatocellular carcinoma. However, TDO inhibition alone is often insufficient because residual pathway flux sustains the accumulation of the downstream immunosuppressive metabolite quinolinic acid (QA). Here, we propose a strategy to disrupt residual kynurenine pathway activity to enhance metabolism-driven tumor immunotherapy. We develop acid-responsive metal-organic complex nanoparticles (APAP@TDOi-Zn, ATZn) that integrate the TDO inhibitor (TDOi) and Zn<sup>2+</sup>, while encapsulating acetaminophen (APAP) to inhibit 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), thereby limiting QA production and simultaneously suppressing the residual immunosuppressive metabolite. QA suppression limits M2 macrophage polarization, whereas Kyn inhibition and Zn<sup>2+</sup> supplementation promote T cell proliferation and cytotoxicity. Consequently, ATZn rewires Trp-Kyn metabolism and augments antitumor immunotherapy. This work enhances the efficacy of metabolic checkpoint blockade and provides a strategy to overcome metabolism-driven immune resistance.</p>

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Inhibition of residual kynurenine pathway activity boosts antitumor immune responses

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Fan Wu,
  • Guangming Xiang,
  • Jing Zhang,
  • Leilei Ying,
  • Hang Ruan,
  • Yiling Wu,
  • Xuehao Wei,
  • Yelin Wu,
  • Yanyan Liu,
  • Ruicheng Shi,
  • Xingwu Jiang

摘要

Immunosuppressive metabolites are major drivers of tumor immune suppression. Among these, kynurenine (Kyn) is produced through the catalysis of tryptophan (Trp) 2,3-dioxygenase (TDO) in hepatocellular carcinoma. However, TDO inhibition alone is often insufficient because residual pathway flux sustains the accumulation of the downstream immunosuppressive metabolite quinolinic acid (QA). Here, we propose a strategy to disrupt residual kynurenine pathway activity to enhance metabolism-driven tumor immunotherapy. We develop acid-responsive metal-organic complex nanoparticles (APAP@TDOi-Zn, ATZn) that integrate the TDO inhibitor (TDOi) and Zn2+, while encapsulating acetaminophen (APAP) to inhibit 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), thereby limiting QA production and simultaneously suppressing the residual immunosuppressive metabolite. QA suppression limits M2 macrophage polarization, whereas Kyn inhibition and Zn2+ supplementation promote T cell proliferation and cytotoxicity. Consequently, ATZn rewires Trp-Kyn metabolism and augments antitumor immunotherapy. This work enhances the efficacy of metabolic checkpoint blockade and provides a strategy to overcome metabolism-driven immune resistance.