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

Junyu Xiang1, Tao Wang2, Shuoran Tian2

  • 1Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Chongqing, China. xiangjunyu1990@126.com.

Nature Cell Biology
|April 3, 2026
PubMed

Insights

Inflammatory cytokines hijack cancer

Area of Science:

  • Cancer Biology
  • Immunology
  • Molecular Signaling

Background:

  • mTORC1 activation by amino acids (AAs) is crucial for cell growth.
  • Environmental cues can rewire intracellular nutrient-sensing pathways.
  • The role of inflammatory signals in cancer's nutrient sensing remains unclear.

Purpose of the Study:

  • To investigate how inflammatory cytokines in the tumor microenvironment (TME) affect cancer-intrinsic AA-sensing mTORC1 signaling.
  • To elucidate the mechanism by which ZBTB5 mediates inflammatory signals to restore mTORC1.
  • To explore the therapeutic potential of targeting the ZBTB5-mTORC1 axis in cancer immunotherapy.

Main Methods:

  • Investigated the role of ZBTB5 in translating inflammatory signals to mTORC1.
  • Utilized biochemical assays to demonstrate ZBTB5-mediated disruption of the GATOR1 complex via NPRL2 degradation.
  • Assessed the impact of ZBTB5-pS127 on tumor cell AA uptake, CD8+ T cell function, and response to immune-checkpoint inhibitors.

Main Results:

  • Inflammatory cytokines hijack cancer mTORC1 signaling via ZBTB5, even in nutrient-poor conditions.
  • ZBTB5-S127 phosphorylation recruits Cullin3ZBTB5 to degrade NPRL2, reactivating mTORC1.
  • This aberrant signaling boosts tumor AA uptake, leading to CD8+ T cell death, immunoevasion, and resistance to immunotherapy.

Conclusions:

  • Targeting ZBTB5-pS127 can overcome primary and acquired resistance to checkpoint blockade.
  • Blocking ZBTB5-pS127 alleviates AA restriction in the TME, sensitizing tumors to immunotherapy.
  • The ZBTB5-pS127-mTORC1 axis is a novel target for enhancing cancer immunotherapy efficacy.

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