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

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.