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<p>Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5–S127, thereby recruiting the Cullin3<sup>ZBTB5</sup> E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8<sup>+</sup> T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5–pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5–pS127–mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.</p>

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Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine–ZBTB5–mTORC1 axis

  • 期刊论文

  • 发表日期：

    2026年4月3日

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  • Junyu Xiang,
  • Tao Wang,
  • Shuoran Tian,
  • Jinyang Li,
  • Mengyun Luo,
  • Yuzhu Wang,
  • Aibei Du,
  • Xu Chen,
  • Fanxuan Tian,
  • Lei Wang,
  • Yongchao Zhang,
  • Mengyi Han,
  • Wenqing Hou,
  • Xinyu Wang,
  • Tao Hou,
  • Qin Liu,
  • Dongfeng Chen,
  • Liangzhi Wen,
  • Zhongyi Qin,
  • Xianfeng Li,
  • Cong Jiang,
  • Qiaoqiao Zhang,
  • Pengda Liu,
  • Xiuwu Bian,
  • Wenyi Wei,
  • Bin Wang

摘要

Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5–S127, thereby recruiting the Cullin3ZBTB5 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8+ T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5–pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5–pS127–mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.