Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma
Shun Wang, Zhu Le, Tianen Li, Xinxin Lin, Yan Zheng, Da Xu, Yu Guo, Ze Zhang, Yan Fu, Hao Wang, Xufeng Wang, Tiantian Zou, Xiaotian Shen, Lumin Zhang, Nannan Lai, Lu Lu, Lun–Xiu Qin, Qiongzhu Dong
Abstract
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, we demonstrate that HCC with high MER proto-oncogene tyrosine kinase (MerTK) expression exhibits anti-PD-1/PD-L1 resistance in two syngeneic mouse models and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, MerTK renders HCC resistant to anti-PD-1/PD-L1 by limiting ferroptosis with the upregulation of SLC7A11 via the ERK/SP1 pathway and facilitating the development of an immunosuppressive tumor microenvironment (TME) with the recruitment of myeloid-derived suppressor cells (MDSCs). Sitravatinib, an inhibitor of MerTK, sensitizes resistant HCC to anti-PD-L1 therapy by promoting tumor ferroptosis and decreasing MDSC infiltration into the TME. In conclusion, we find that MerTK could serve as a predictive biomarker for patient stratification and as a promising target to overcome anti-PD-1/PD-L1 resistance in HCC. • MerTK renders anti-PD-1/PD-L1 therapy resistance in HCC • MerTK suppresses tumor cell ferroptosis and induces an immunosuppressive TME • Inhibition of MerTK increases the efficacy of PD-L1 antibody • Combination of sitravatinib and PD-L1 antibody has a synergistic antitumor effect Dong et al. report that MerTK upregulates SLC7A11 expression to suppress tumor cell ferroptosis, favors a protumor TME by recruiting MDSCs in hepatocellular carcinoma (HCC), and drives anti-PD-L1 therapy resistance. Targeting MerTK increases ferroptosis and reduces MDSCs recruitment, which activates CD8 + T cells and sensitizes HCC to anti-PD-L1 blockade.