Cancer SLC3A2-mediated lysine uptake restricts T cell immunity against hepatocellular carcinoma

Our research demonstrates that in hepatocellular carcinoma (HCC), tumor cells outcompete T cells for lysine (Lys) by overexpressing the SLC3A2 transporter, thereby reducing Lys availability within the tumor microenvironment. This lysine deprivation results in decreased STAT3 levels in T cells, inhibiting their proliferation and effector functions, which ultimately accelerates tumor progression. Additionally, we identified a c-Myc-SLC3A2 regulatory axis activated by Lenvatinib, enhancing the sensitivity of HCC to the combined treatment with Lenvatinib and Lys. RNA sequencing (RNA-seq) was performed on CD3+ T cells cultured in fresh medium, Hepa1-6 supernatants, and Hepa1-6 supernatants supplemented with lysine. RNA-seq on control and SLC3A2 knockdown lentivirus-treated Huh-7 cells.