Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma.

Background: Lenvatinib was expected to enhance the effect of immune checkpoint inhibitors (ICIs) for unresectable HCC; however, their combination therapy failed to show the synergy in the phase III clinical trial.

Methods: To elucidate lenvatinib-induced molecular modulation, we performed bulk RNA-sequencing and digital spatial profiling of 5 surgically resected human HCC specimens after lenvatinib treatment and 10 matched controls without any preceding therapy.

Findings: Besides its direct antitumor effects, lenvatinib recruited cytotoxic GZMK+CD8 T cells in intratumor stroma by CXCL9 from tumor-associated macrophages, suggesting that lenvatinib-treated HCC is in the so-called excluded condition that can diminish ICI efficacy.