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<p>CD8<sup>+</sup> T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING–TOX–HO-1-mediated CD8<sup>+</sup> T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance.</p>

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STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月9日

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  • Qian Zhu,
  • Jun-bao Zhang,
  • Cai-ping Nie,
  • Xiu-feng Liu,
  • Liang-ping Zhan,
  • Ming Li,
  • Xi-liang Zeng,
  • Jia He,
  • He Huang,
  • Xiao-jun Xia,
  • Song Gao,
  • Xiao-shi Zhang,
  • Jiang Li

摘要

CD8+ T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING–TOX–HO-1-mediated CD8+ T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance.