Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis PMID: 41933211

ADC Targets in Oncology

2026-04-10

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

Nat Cell Biol. 2026 May;28(5):1000-1014. doi: 10.1038/s41556-026-01926-8.

Junyu Xiang ^# ¹ , Tao Wang ^# ² , Shuoran Tian ^# ² , Jinyang Li ² , Mengyun Luo ² , Yuzhu Wang ² , Aibei Du ² , Xu Chen ² ³ , Fanxuan Tian ² , Lei Wang ² , Yongchao Zhang ² , Mengyi Han ² , Wenqing Hou ² , Xinyu Wang ² , Tao Hou ⁴ , Qin Liu ² , Dongfeng Chen ² , Liangzhi Wen ² , Zhongyi Qin ² , Xianfeng Li ² , Cong Jiang ⁴ ⁵ , Qiaoqiao Zhang ³ , Pengda Liu ⁶ , Xiuwu Bian ⁷ ⁸ , Wenyi Wei ⁹ , Bin Wang ¹⁰ ¹¹ ¹²

Affiliations

1. Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Chongqing, China. [email protected].
2. Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Chongqing, China.
3. Jinfeng Laboratory, Chongqing, China.
4. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
5. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
6. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
7. Jinfeng Laboratory, Chongqing, China. [email protected].
8. Institute of Pathology and Southwest Cancer Center, Southwest Hospital and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. [email protected].
9. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
10. Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Chongqing, China. [email protected].
11. Jinfeng Laboratory, Chongqing, China. [email protected].
12. Institute of Pathology and Southwest Cancer Center, Southwest Hospital and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. [email protected].
# Contributed equally.

Abstract

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^ZBTB5 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.