Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer

作者：Ting Liu, Fanxin Zeng, Zuyin Li, Leirong Cheng, Xuanxuan Yan, Haiqiang Chen, Qin Liu, Xue Li, Li Zhao, Jiaheng Yao, Dan Xu, Zhi‐Nan Chen, Fengchao Wang, Jun Wang, Jinhua Zhang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-67344-w · 被引用次数：2 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers

Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b−/−) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC. Mechanism of CD8 T cell dysfunction in tumor microenvironment requires continuous investigation. The authors here show that Lypd6b expression is increased in CD8 T cells of colorectal cancer tissue and its absence inhibits MC38 or CMT-93 tumor growth associated with upregulated glycolysis a...