DUSP22 dephosphorylates LGALS1 to enhance T cell-driven antitumor immunity

作者：Lijian Wang, Yutong Guo, Yujie Dai, Wangsheng Sun, Xiaoying Huang, Haipeng Lei, Aiping Zhang, Shuwen Chen, Yiming Li, Jiani Pan, Yangjian Hong, Lingchuan Ma, Yangyang Feng, Fangyuan Shao, Jianming Zeng, Peng Luo, Junqi Li, Weiting Chen, Na Zhou, Yiming Li, Heng Sun, Xiaoling Xu, Chu-Xia Deng, Kai Miao · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2026 · DOI：10.1136/jitc-2025-013142 · 被引用次数：1 · 研究领域：Protein Tyrosine Phosphatases、Cancer Immunotherapy and Biomarkers、Phagocytosis and Immune Regulation

Background Insufficient infiltration of CD8 + T cells in the tumor microenvironment (TME) critically restricts antitumor immunity and cancer immunotherapy efficacy. The purpose of this study was to identify novel tumor cell-intrinsic regulators of T-cell infiltration and to elucidate their mechanisms of action. Methods We performed a genome-wide Sleeping Beauty transposon mutagenesis screen in murine breast cancer models. Protein–protein interactions were identified by mass spectrometry and validated by co-immunoprecipitation. Gene and protein expression levels were assessed by reverse transcription and quantitative PCR and western blotting. T-cell infiltration and function were evaluated using flow cytometry, immunohistochemistry (IHC), multiplex IHC, and by analyzing bulk and single-cell RNA sequencing data complemented by bioinformatic analysis. The specific dephosphorylation sites on LGALS1 were confirmed through phosphomimetic mutant experiments. T-cell infiltration was further validated using an in vitro T-cell transendothelial migration assay and in vivo mouse models. Results Our screening identified 39 candidate genes, with tumor cell-intrinsic dual-specificity phosphatase 22 (DUSP22) expression correlating with enhanced CD8 + T-cell accumulation and suppressed tumor progression. Overexpression of DUSP22 resulted in increased CD8 + T-cell infiltration and enhanced T-cell function. Mechanistically, DUSP22 binds to LGALS1 and dephosphorylates it at the Ser8 and Thr58 re...