Mingyu Liu’s research while affiliated with University of Jinan and other places

Purpose Hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib (Len) and immune checkpoint inhibitor (ICI) in treating advanced hepatocellular carcinoma (HCC) still needs further confirmation. We aimed to evaluate the efficacy of HAIC combined with Len and ICI (HAIC + Len + ICI) versus Len alone in advanced HCC. Methods A total of 290 patients in Len group and 349 patients in HAIC + Len + ICI group were analysed. Propensity score matching (PSM), inverse probability treatment weighting (IPTW), and coarsened exact matching (CEM) analyses were used to balance the bias between two groups. Mediation analysis of treatment type in survival was performed for analysis. Results The median progression-free survival (PFS) was 5.9 ± 0.2 months in Len group and 9.2 ± 0.5 months in HAIC + Len + ICI group. The HAIC + Len + ICI group demonstrated significantly better PFS than the Len group across the entire cohort (hazard ratio [HR], 0.50; 95% CI 0.43–0.60; P < 0.001). This advantage in PFS was sustained in the PSM, IPTW, and CEM cohorts. HAIC + Len + ICI group also showed better overall survival (OS) than the Len group (HR, 0.38; 95% CI 0.31–0.46; P < 0.001). The OS was also superior in the PSM, IPTW, and CEM cohorts. The objective response rate (ORR) in HAIC + Len + ICI group was twice as high as that in Len group. Further mediation analysis showed tumor response at 3 and 6 months had different mediation effect on survival. Conclusions HAIC combined with Len and ICI showed improved better OS and PFS than Len alone. This triple therapy could be considered as a first-line treatment for advanced HCC.

Background Liver cancer has a high global incidence, particularly in East Asia. Early detection difficulties lead to poor prognosis. Single-cell sequencing precisely identifies gene expression differences in specific cell types, making it valuable in tumor microenvironment research and immune drug development. However, the characteristics of tumor cells themselves are equally important for patient prognosis and treatment. Methods We downloaded single-cell sequencing data from GSE189903, grouped cells by cluster markers, and classified epithelial cells into adjacent non-tumor, normal, and tumor cells. Differential gene and survival analyses identified significant differential genes. Using TCGA-LIHC data, we divided 370 patients into test and training sets. We constructed and validated a LASSO model based on these genes in both sets and two external datasets. Functional, immune infiltration, and mutation analyses were performed on high and low-risk groups. We also used RNA-seq and IC50 data of 15 liver cancer cell lines from GDSC, scoring them with our prognostic model to identify potential drugs for high-risk patients. Results Dimensionality reduction and clustering of 34 single-cell samples identified five subgroups, with epithelial cells further classified. Differential gene analysis identified 124 significant genes. An 11-gene prognostic model was constructed, effectively stratifying patient prognosis (p < 0.05) and achieving an AUC above 0.6 for 5 year survival prediction in multiple cohorts. Functional analysis revealed that upregulated genes in high-risk groups were enriched in cell adhesion pathways, while downregulated genes were enriched in metabolic pathways. Mutation analysis showed more TP53 mutations in the high-risk group and more CTNNB1 mutations in the low-risk group. Immune infiltration analysis indicated higher immune scores and less CD8 + naive T cell infiltration in the high-risk group. Drug sensitivity analysis identified 14 drugs with lower IC50 in the high-risk group, including clinically approved Sorafenib and Axitinib for treating unresectable HCC. Conclusion We established an 11-gene prognostic model that effectively stratifies liver cancer patients based on differentially expressed genes between tumor and adjacent non-tumor cells clustered by scRNA-seq data. The two risk groups had significantly different molecular characteristics. We identified 14 drugs that might be effective for high-risk HCC patients. Our study provides novel insights into tumor cell characteristics, aiding in research on tumor development and treatment.

Purpose The outcome between Lenvatinib plus programmed cell death protein-1 (PD-1) inhibitor and Lenvatinib in HCC beyond oligometastasis was unclear. In this multicenter, we compared the prognosis of Lenvatinib plus PD-1 inhibitor with Lenvatinib in HCC beyond oligometastasis. Patients and Methods A total of 296 patients from six institutions were included. The patients were divided into two groups: (a) concurrent Lenvatinib plus PD-1 inhibitor treatment (Len+PD-1 group) and (b) Lenvatinib monotherapy (Len group). The primary endpoint was overall survival (OS), the second endpoint was progression-free survival (PFS) and efficacy. Results The median OS was 20.1 ± 1.2 (17.7–22.5) months and 15.7 ± 1.5 (12.8–18.6) months in the Len+PD-1 and Len groups, respectively. The 12-, 24-, and 36-month OS rates were 79.1%, 39.4%, and 10.7% in the Len+PD-1 group, and 76.3%, 29.7%, and 0% in the Len group, respectively. The OS and PFS rates of the Len+PD-1 group were significantly longer compared with the Len group (hazard ratio [HR], 0.88; 95% confidence index [CI], 0.49–0.94; P = 0.021) and (HR, 0.66; 95% CI, 0.50–0.87; P = 0.003). A subgroup analysis revealed that OS (HR, 0.57; 95% CI, 0.36–0.90; P = 0.016) was improved between the Len+PD-1 and Len groups with hepatic artery infusion chemotherapy (HAIC) treatment, whereas OS (HR, 1.11; 95% CI, 0.68–1.80; P = 0.689) was similar between the Len and Len+PD-1 groups without HAIC. Conclusion Lenvatinib combined with PD-1 inhibitor significantly improves the survival of HCC beyond oligometastasis. For patients with HAIC, there was obviously significance between Len and Len+PD-1 groups.

Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, evidence is presented that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of postablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME). To address this, an injectable nanoparticles‐hydrogel composite system (LOX‐MnO2@Gel) is designed that gradually releases lactate oxidase (LOX)‐loaded hollow mesoporous MnO2 nanoparticles at the tumor site to continuously deplete intratumoral lactate via a cascade catalytic reaction. Using subcutaneous and orthotopic HCC tumor‐bearing mouse models, it is confirmed that LOX‐MnO2@Gel‐mediated local lactate depletion can transform the immunosuppressive postablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis, thereby prolonging the survival of mice postablation. The work proposes an appealing strategy for synergistically combining antitumor metabolic therapy with immunotherapy to combat postablative HCC recurrence.

Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-β1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-β1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-β1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-β1. In conclusion, IFN-γ induced TGF-β1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIP/TGF-β1/Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis. CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP. CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.

Hepatic stellate cells (HSCs) play key roles in liver fibrosis (LF) and hepatocellular carcinoma (HCC). We previously reported that spleen tyrosine kinase (SYK) is critical for HSCs activation, however, the mechanisms are insufficiently understood. In the present study, we found that SYK facilitated autophagy to promote HSCs activation by enhancing reactive oxygen species (ROS) generation. However, SYK inhibitor GS-9973 could efficiently reduce HSCs ROS generation in vitro but not in vivo. Mechanistically, hepatocytes (HCs) would release ROS outside and then diffuse into HSCs to promote autophagy and activation in vitro in the context of inflammation. We then further examined the ROS contents in liver sections and primary liver cells of carbon tetrachloride (CCl4) induced mice treated with or without different doses of Silybin, a natural compound characterized by a well-established antioxidant and hepatoprotective properties, and found that ROS intensities in both liver sections and their deprived primary cells were efficiently inhibited in a dose-dependent fashion. Lastly, we evaluated the rational combination of Silybin and GS-9973 in the treatment of CCl4 induced mice and found that this combination is well tolerated and acts synergistically against HSCs activity, LF and HCC. The combinational use of Silybin and GS-9973 could be a promising therapeutic strategy in patients suffering from LF and even HCC.

The malignant transformation of residual hepatocellular carcinoma (HCC) cells after thermal ablation is considered as the main factor promoting postoperative HCC progression, which greatly limits the improvement of long-term survival, and at present there is no effective targeted therapeutic strategies. The Warburg effect is a metabolic feature correlated highly with malignant transformation (e.g. epithelial-to-mesenchymal transition [EMT]). Here, we showed that sublethal heat stress triggered a stronger Warburg effect of HCC cells, which contributed to the thermotolerance and invasion of HCC cells. Sublethal heat stress-induced O-GlcNAcylation was involved in this process. Such enhanced Warburg effect in HCC cells may be eliminated through O-GlcNAcylation inhibition, resulting in impaired thermotolerance and EMT, and thereby preventing tumor recurrence and metastasis of HCC-bearing mice after insufficient thermal ablation. Finally, we present evidence that sublethal heat stress-induced O-GlcNAcylation regulates the Warburg effect in HCC cells by promoting hypoxia-inducible factor 1α (HIF-1α) stability. In conclusion, the present study suggests that O-GlcNAcylation coordinates the Warburg effect to promote HCC progression after thermal ablation, which may serve as a novel potential target for controlling postoperative HCC recurrence and metastasis.