Siglec‐G Suppresses CD8<sup>+</sup> T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
Shenhui Yin, Chunzhen Li, Xin Shen, Guanyu Yu, Likun Cui, Yunyang Wu, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Cheng Qian, Zui Zou, Yizhi Yu, Sheng Xu
Abstract
Abstract CD8 + T cells play a critical role in cancer immune‐surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death‐1 (PD‐1) and T cell immunoglobulin domain and mucin domain‐3 (Tim‐3). Here Siglec‐G is identified as a coinhibitory receptor that limits CD8 + T cell function. Siglec‐G is highly expressed on tumor‐infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec‐G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec‐G‐SHP2 axis in CD8 + T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec‐G in inhibiting CD8 + T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.