@article{APS11618,
author = {Ju-fei Li and Hao Wang and Ling Kang and Cheng-cheng Xu and Yuan-chun Liu and Zi-xuan Li and Shao-hao Lin and Ming-zhi Wang and Xiao-min Xu and Pei-pei Wang and Wan-chao Yin and Yu-bo Zhou and Yu Zhou and Jia Li},
title = {Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 + reactivates CD8 T cell immunity and suppresses tumor growth},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {9},
year = {2026},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11618}
}