Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 + reactivates CD8 T cell immunity and suppresses tumor growth
Ju-fei Li1,2,
Hao Wang3,4,
Ling Kang5,
Cheng-cheng Xu2,6,
Yuan-chun Liu7,
Zi-xuan Li3,4,
Shao-hao Lin8,
Ming-zhi Wang6,
Xiao-min Xu2,
Pei-pei Wang6,9,
Wan-chao Yin2,4,10,
Yu-bo Zhou2,4,11,
Yu Zhou3,4,
Jia Li1,2,4,5,6,12
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 Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
11 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
12 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to: Wan-chao Yin: wcyin@simm.ac.cn, Yu-bo Zhou: ybzhou@simm.ac.cn, Yu Zhou: zhouyu@simm.ac.cn, Jia Li: jli@simm.ac.cn,
DOI: 10.1038/s41401-026-01843-4
Received: 19 September 2025
Accepted: 30 April 2026
Advance online: 8 June 2026
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:
interleukin-4-induced-1 (IL4I1); aryl hydrocarbon receptor (AHR); tryptophan metabolism; tumor immune
