Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression.

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

Sun P ，Li Z ，Yan Z ，Wang Z ，Zheng P ，Wang M ，Chang X ，Liu Z ，Zhang J ，Wu H ，Shao W ，Xue D ，Yu J ... -  《BMC CANCER》

β,β-Dimethylacrylalkannin, a Natural Naphthoquinone, Inhibits the Growth of Hepatocellular Carcinoma Cells by Modulating Tumor-Associated Macrophages.

Shen LS ，Lin Z ，Gong RH ，Lin YS ，Qiao XF ，Hu QM ，Qin WH ，Chen S ，Yang Y ，Chen GQ ... -  《MOLECULES》

STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib.

Zheng Y ，Huang C ，Lu L ，Yu K ，Zhao J ，Chen M ，Liu L ，Sun Q ，Lin Z ，Zheng J ，Chen J ，Zhang J ... -  《Journal of Hematology & Oncology》

Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo.

Nuclear factor-kappa B (NF-κB), an oncogenic transcription factor, modulates tumor formation and progression by inducing the expression of oncogenes involved in proliferation, survival, angiogenesis, and metastasis. Oral multikinase inhibitors, such as sorafenib, regorafenib, and lenvatinib have been used for the treatment of hepatocellular carcinoma (HCC). Both sorafenib and regorafenib were shown to abolish the NF-κB-mediated progression of HCC. However, the effect of lenvatinib on NF-κB-mediated progression of HCC is ambiguous. Therefore, the primary purpose of the present study was to evaluate the inhibitory effect of lenvatinib and its inhibitory mechanism on the NF-κB-mediated progression of HCC in vitro and in vivo. Here, we used two HCC cell lines to identify the cytotoxicity, apoptosis and metastasis effect of lenvatinib. We also applied a Hep3B-bearing animal model to investigate the therapeutic efficacy of lenvatinib on in vivo model. An NF-κB translocation assay, NF-κB reporter gene assay, a Western blotting assay and immunohistochemistry staining were used to investigate the underlying mechanism by which lenvatinib acts on HCC. In this study, we demonstrated that lenvatinib induced extrinsic/intrinsic apoptosis and suppressed the metastasis of HCC both in vitro and in vivo. Lenvatinib may also suppress NF-κB translocation and activation. We also found both protein kinase C delta (PKC-δ) and p38 mitogen-activated protein kinase (MAPK) inactivation participated in lenvatinib-reduced NF-κB signaling. In conclusion, this study reveals that the suppression of PKC-δ, and the p38 MAPK/NF-κB axis is associated with the lenvatinib-inhibited progression of HCC in vitro and in vivo.

Wu CH ，Hsu FT ，Chao TL ，Lee YH ，Kuo YC ... -  《-》

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8(+) T cells in hepatocellular carcinoma.

The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Zhu CX ，Yan K ，Chen L ，Huang RR ，Bian ZH ，Wei HR ，Gu XM ，Zhao YY ，Liu MC ，Suo CX ，Li ZK ，Yang ZY ，Lu MQ ，Hua XF ，Li L ，Zhao ZB ，Sun LC ，Zhang HF ，Gao P ，Lian ZX ... -  《-》