In recent years, tumor immunity**, represented by immune checkpoint inhibitors (ICIS), has been considered one of the most successful methods in the field of cancer**, but the benefit to patients is limited, and even after patients have benefited, drug resistance can still occur.
On February 20, 2024, Dong Qiongzhu, Qin Lunxiu, and Lu Lu of Fudan University jointly published a joint newsletter titled "Disruption of Mertk Increases the Efficacy of Checkpoint Inhibitor by Enhancing Ferrotosis and Immune Response In" in Cell Reports Medicine** Hepatocellular Carcinoma", which showed that targeting MERTK could improve the efficacy of immune checkpoint inhibitors by enhancing ferroptosis and immune responses in hepatocellular carcinoma.
In this study, the researchers demonstrated that the MER proto-oncogene tyrosine kinase (MERTK) was highly expressed in two ICI-resistant mouse models of HCC and in HCC patients who received anti-PD-1 PDL1**, and that MERTK is one of the "culprits" leading to ICIS resistance in HCI. Mechanistically, MERTK inhibits ferroptosis in hepatoma cells by upregulating the expression of SLC7A11 through the ERK SP1 pathway, and promotes the formation of immunosuppressive tumor microenvironment (TME) in hepatocellular carcinoma by recruiting myeloid-derived suppressor cells (MDSCs), thereby making hepatocellular carcinoma resistant to PD-1 PD-L1. Sitr**atinib is an inhibitor of MERTK that sensitizes drug-resistant HCCs against PD-L1** by promoting ferroptosis in tumor cells and reducing the infiltration of MDSC into TME.
Hepatocellular carcinoma (HCC) remains a global health challenge, with an increasing incidence worldwide. Clinically, most HCC patients are diagnosed with advanced disease, with limited options. Recently, immune**, such as ICIS anti-CTLA4, anti-PD-1 PD-L1, their combinations or in combination with other drugs, have achieved unparalleled success in cancer patients. In addition, ICIS such as nivolumab, pembrolizumab, and atezolizumab are currently approved by the FDA for systemic HCC**. However, response rates remain far from satisfactory due to the frequent emergence of resistance to anti-PD-1 PD-L1**, and an overall benefit rate has been observed in only about 15% to 20% of HCC patients. Therefore, there is an urgent need to identify the best biomarkers for patient selection and identify effective targets to overcome this resistance. Mertk is a member of the tyrosine receptor kinase TAM family (Tyro3, AXL, and MertK) and is highly expressed in a variety of malignancies, including HCC (The Human Protein Atlas: ProteinAtlasorg)。Homologous protein growth inhibition specific protein 6 (GAS6) and protein S (PROS1) are natural ligands for MERTK activation, which can induce homodimerization and autophosphorylation of MERTK, activate downstream pathways such as MEK ERK, PI3K AKT, and JAK STAT, thereby promoting tumor cell proliferation, anti-apoptosis, inhibiting inflammation and tumor malignant processes. Recent studies have shown that MERTK, as a metabolic regulator, plays a key role in regulating HCC growth by integrating aerobic glycolysis and oxidative phosphorylation. In addition, the receptor ligand activity of MERTK has been demonstrated in a variety of immune cell types and has important implications for the immunity of cancer**.
Mechanistic model diagram (Figure courtesy of Cell Reports Medicine) Ferroptosis, as a metabolically regulated form of cell death, plays an important role in cancer biology. In recent years, there has been growing evidence that inhibition of ferroptosis is closely related to resistance to conventional cancers**, and that targeting ferroptosis may provide potential for cancer**. Recently, studies have shown that regulation of ferroptosis during the immuno** process can remodel the tumor immune microenvironment, leading to T cell-mediated tumor elimination. In HCC, ferroptosis has been shown to be associated with resistance to tumors** (e.g., targeted** and chemotherapy). This study showed that MERTK upregulated SLC7A11 expression and inhibited ferroptosis in tumor cells, while promoting tumor TME by recruiting MDSCs in the HCC microenvironment, leading to anti-PD-L1** resistance. Targeting MERTK is an effective strategy to improve the effectiveness of PD-L1 antibodies**. In PD-L1-resistant hepatocellular carcinoma, the combination of the MERTK inhibitor Sitr**atinib and ICIS can effectively increase ferroptosis of tumor cells, reduce MDSCS recruitment in the liver cancer microenvironment, and promote CD8+ T cell activation. In conclusion, the study suggests that MERTK can be used as a ** marker of ICB efficacy and is a potential target to overcome anti-PD-1 PD-L1 resistance in HCC. Original link: