Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1 + CD8 + T cells in HCC via blocking VEGFR2

Lenvatinib is the favorable treatment for advanced hepatocellular carcinoma (HCC), and it is currently undergoing phase III clinical trials. However, the specific effects of lenvatinib on PD1+ CD8+ T cells in HCC microenvironment have not been systematically studied. Here, we established an orthotopic hepa1-6 mouse model treated with lenvatinib to investigate CD8+ T cells' role in the tumor and spleen. We found an increasing proportion of TCF-1+ in PD1+ CD8+ T cells and proliferation of PD1+ CD8+ T cells after lenvatinib treatment. Meanwhile, lenvatinib treatment upregulated the expression of granzyme B on PD1+ CD8+ T cells both in vitro and in vivo. Lenvatinib activated the endogenous mTOR pathway of exhausted CD8+ T cells, and mTOR pathway blockade eliminated the antitumor effect of lenvatinib and function of PD1+ CD8+ T cells. The effects of the mTOR pathway on PD1+ CD8+ T cells after lenvatinib treatment were mediated by VEGFR2 inhibition. Overall, our work provides insight into the mechanism of lenvatinib's antitumor efficacy through exhausted CD8+ T cells in HCC treatment.