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Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatments and ranks as the second most lethal tumor. Immunotherapy has brought great hope for HCC treatment. Oxysophocarpine is a bioactive alkaloid which poses various pharmacological functions including neuroprotective, anti‐virus, anti‐convulsant, and anti‐nociception. However, there is little systematic study of Oxysophocarpine against HCC and its underlying potential and mechanism combined with immunotherapy in HCC treatment remain poorly unknown. This study was aimed to investigate whether Oxysophocarpine can distinctly suppress HCC cells and sensitize the immunotherapy of CD8+ T cells against HCC. We used HepG2, Hepa1‐6, and primary CD8+ T cells to perform in vitro assays and Hepa1‐6 subcutaneous tumor to conduct in vivo assay. Oxysophocarpine inhibited the proliferation and increased the apoptosis of HepG2 and Hepa1‐6 cells, meanwhile suppressed the migration of HepG2 and Hepa1‐6 cells. Oxysophocarpine sensitized the Lag‐3 immunotherapy effect of CD8+ T cells against HCC in vivo and in vitro by decreasing Fibrinogen‐like protein 1 (FGL1) expression through downregulating IL‐6‐mediated JAK2/STAT3 signaling, whereas Oxysophocarpine treatment had a little effect of CD8+ T cells cytotoxicity function against HCC with PD‐1, Tim‐3, or TIGIT blockade. Our studies provided preclinical basis for clinical application of Oxysophocarpine., Oxysophocarpine inhibited the proliferation, migration, and increased the apoptosis of HCC cells. Oxysophocarpine sensitized the Lag‐3 immunotherapy effect of CD8+ T against HCC by decreasing FGL1 expression through IL‐6‐mediated JAK2/STAT3 pathway.

Background/Aims: Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oncogene in various types of cancers, including oral squamous cell carcinoma (OSCC). Oxysophocarpine (OSC) is a natural alkaloid that has multiple pharmacological activities. However, the biological functions and molecular mechanism underlying the effects of OSC on the growth and metastasis of OSCC are unclear. Methods: Nrf2 levels were determined in OSCC tissues and non-cancerous specimens by quantitative real-time PCR, western blotting, and immunohistochemistry (IHC) assays. The effects of OSC on OSCC cell growth and metastasis were explored (1) using 5-ethynyl-20-deoxyuridine staining and Cell Counting Kit-8, colony formation, flow cytometry, wound-healing, Transwell, and tube formation assays in vitro; and (2) by establishing a xenograft nude mouse model in vivo. The molecular mechanisms underlying the effects of OSC on the growth and metastasis of OSCC were investigated in vitro by western blotting, caspase-3 activity, and enzyme-linked immunosorbent assays, and in vivo by western blotting and IHC assays. Results: The expression levels of Nrf2 in OSCC tissues and in cell lines were much higher than in non-cancerous tissues and normal oral keratinocytes. The upregulation of Nrf2 was positively correlated with a high incidence of lymph node metastasis and advanced histological grade and TNM stage, but inversely associated with differentiation and survival of OSCC patients. OSC reduced the expression of Nrf2 and heme oxygenase 1 (HO-1) in OSCC cells. OSC also inhibited proliferation, migration, invasion, and pro-angiogenesis of OSCC cells. Moreover, OSC induced cell cycle arrest, enhanced apoptosis of OSCC cells in vitro, and decreased OSCC tumor growth in vivo. Mechanically, OSC reduced the aggressive behavior of OSCC cells by inactivation of the Nrf2/HO-1 signaling pathway. Conclusion: Our findings provide evidence that OSC inhibits the growth and metastasis of OSCC by targeting the Nrf2/ HO-1 axis, suggesting that OSC may be a potential therapeutic agent for OSCC.