Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 reactivates CD8+ T cell immunity and suppresses tumor growth PMID: 42252303

ADC Targets in Oncology

2026-04-10

Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 reactivates CD8+ T cell immunity and suppresses tumor growth

Acta Pharmacol Sin. 2026 Jun 8. doi: 10.1038/s41401-026-01843-4.

Ju-Fei Li ^# ¹ ² , Hao Wang ^# ³ ⁴ , Ling Kang ^# ⁵ , Cheng-Cheng Xu ^# ² ⁶ , Yuan-Chun Liu ⁷ , Zi-Xuan Li ³ ⁴ , Shao-Hao Lin ⁸ , Ming-Zhi Wang ⁶ , Xiao-Min Xu ² , Pei-Pei Wang ⁶ ⁹ , Wan-Chao Yin ¹⁰ ¹¹ ¹² , Yu-Bo Zhou ¹³ ¹⁴ ¹⁵ , Yu Zhou ¹⁶ ¹⁷ , Jia Li ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²³

Affiliations

1. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
2. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
3. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
4. University of Chinese Academy of Sciences, Beijing, 100049, China.
5. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
7. College of Life Science and Technology, Xinjiang University, Xinjiang, 830046, China.
8. School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
9. Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
10. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. [email protected].
11. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
12. Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
13. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. [email protected].
14. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
15. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
16. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
17. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
18. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
19. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. [email protected].
20. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
21. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. [email protected].
22. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. [email protected].
23. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
# Contributed equally.

Abstract

Metabolic hijacking of tryptophan (Trp) via the IL4I1-AHR axis is a pivotal immune evasion mechanism in cancers, yet therapeutic strategies to disrupt this pathway remain unexplored. Here, we report the identification of ZY-MY-111, a selective small-molecule inhibitor of interleukin-4-induced-1 (IL4I1), through an in-house compound library screening and structural optimization. ZY-MY-111 exhibits potency (IC₅₀ = 1.86 ± 0.13 μM) in blocking IL4I1-mediated oxidative deamination. Mechanistically, ZY-MY-111 acts as a mixed-type inhibitor, competitively occupying the catalytic pocket of IL4I1 and disrupting Trp-AHR signaling in cells. Functionally, ZY-MY-111 promotes T cell proliferation, enhancing immune responses against the tumor cells. In syngeneic tumor models, ZY-MY-111 achieved 49% tumor growth inhibition in CT26 colon carcinoma (P < 0.001) and 56% tumor growth inhibition in A20 lymphoma (P < 0.001) by remodeling the immunosuppressive microenvironment: increasing CD8⁺/CD4⁺ T cell ratios, reducing myeloid-derived suppressor cells (MDSCs, 59% decrease), and enhancing effector memory T cell infiltration. Our findings position IL4I1 inhibition as a potential strategy to restore anti-tumor immunity.

Keywords

CD8+ T cells; aryl hydrocarbon receptor (AHR); immunotherapy; interleukin-4-induced-1 (IL4I1); tryptophan metabolism; tumor immune microenvironment.