Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.

High Expression of Ten Eleven Translocation 1 Is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Background: DNA methylation patterns have been found to be distinct between tumor and normal patients. However, the effect of DNA demethylation enzymes, ten eleven translocation (TET) proteins, has not been comprehensively characterized in liver cancer. In this research, we sought to unravel the linkage of TET proteins with prognosis, immune characteristics and biological pathways in hepatocellular carcinoma (HCC). Materials and Methods: Four independent datasets with gene expression data and clinical data of HCC samples were downloaded from public databases. CIBERSORT, single sample Gene Set Enrichment Analysis (ssGSEA), MCP-counter, and TIMER were implemented to evaluate immune cell infiltration. limma was employed to screen differentially expressed genes (DEGs) between two groups. The demethylation-related risk model was established by using univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO), and stepwise Akaike information criterion (stepAIC). Results: TET1 was significantly higher expressed in tumor samples than that in normal samples. HCC patients with advanced stages (III+IV) and grades (G3+G4) had higher TET1 expression compared to early stages (I+II) and grades (G1+G2). HCC samples with high TET1 expression had worse prognosis than that with low expression. High and low TET1 expression groups had distinct immune cell infiltration and response to immunotherapy and chemotherapy. We identified 90 DEGs related to DNA demethylation in high vs. low TET1 expression groups. Furthermore, we established a risk model based on 90 DEGs containing seven key prognostic genes (SERPINH1, CDC20, HACD2, SPHK1, UGT2B15, SLC1A5, and CYP2C9) with effectiveness and robustness in predicting HCC prognosis. Conclusions: Our study suggested TET1 as a potential indicator in HCC progression. TET1 was closely involved in immune infiltration and activation of oncogenic pathways. The DNA demethylation-related risk model was potential to be applied for predicting HCC prognosis in clinics.

Slit2 signaling contributes to cholestatic fibrosis in mice by activation of hepatic stellate cells.

Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis. Our findings revealed that the serum levels and hepatic expression of Slit2 were significantly increased in patients with primary biliary cirrhosis (PBC). Additionally, Slit2-Tg mice were much more vulnerable to BDL-induced liver injury and fibrosis compared to WT control. Slit2 up-regulation by Slit2 recombinant protein induced proliferation, and inhibited apoptosis of human HSCs cell line LX-2 via p38 and ERK signaling pathway, resulting in the activation of HSCs. In contrast, Slit2 down-regulation by siRNA silencing inhibit the activation of HSCs. In conclusion, Slit2 is involved in the activation of HSCs and liver fibrogenesis, highlighting Slit2 as a potential therapeutic target for liver fibrosis.

Co-Delivery of Doxorubicin and Anti-BCL-2 siRNA by pH-Responsive Polymeric Vector to Overcome Drug Resistance in In Vitro and In Vivo HepG2 Hepatoma Model.

Drug resistance, developed through multiple mechanisms, is a major hindrance to successful chemotherapy of tumor. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy which may improve anticancer effect by synergistic actions. In this study, triblock copolymer of poly(ethylene glycol)- block-poly(l-lysine)- block-poly aspartyl ( N-( N', N'-diisopropylaminoethyl)) (PEG-PLL-PAsp(DIP)) was synthesized for the first time to enable the codelivery of BCL-2 siRNA and DOX. The system is supposed to not only bypass drug efflux but also down-regulate the antiapoptotic gene and consequently confronting against chemoresistance as well. Moreover, the pH responsive ability of the codelivery system can prevent drug leakage during circulation and guarantee swift drug release at tumors. The codelivered siRNA serves to suppress the expression of antiapoptotic BCL-2 and hence sensitize the cancer cells to anticancer drugs and produce improved therapeutic effect. Consequently, the codelivery of BCL-2 siRNA and anticancer drug DOX serves as a promising strategy against drug resistance in chemotherapy.

Aortic plaque-targeted andrographolide delivery with oxidation-sensitive micelle effectively treats atherosclerosis via simultaneous ROS capture and anti-inflammation.

Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Andrographolide-loaded micelle was assembled from the block copolymer of poly(ethylene glycol) and poly(propylene sulphide) (PEG-PPS) for the purpose of simultaneously decreasing inflammatory response and the level of reactive oxygen species (ROS) to treat atherosclerosis. Owing to the ROS-responsive nature of PEG-PPS, the micelle not only serves as a stimuli-responsive drug carrier to quickly release the encapsulated drug, andrographolide, but also consumes ROS by itself at the pathologic sites, upon which the expressions of pro-inflammatory cytokines are effectively suppressed and oxidative stress is alleviated. Consequently, the andrographolide-loaded micelle demonstrated remarkable therapeutic effects both in vitro and in vivo. In conclusion, the andrographolide-loaded PEG-PPS micelle can synchronically alleviate inflammation and oxidative stress, providing a promising and innovative strategy against atherosclerosis.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.

Manganese oxide-constructed multifunctional biomimetic nanovaccine for robust tumor-specific T cell priming and chemodynamic therapy.

The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy. Compared with the nanovaccines coated with the single cell membrane, the MP@RHM nanovaccine highly efficiently activates both DCs and T cells to boost tumor-specific T cell, owing to the synergistic effects of abundant damage-associated molecular patterns, Mn2+, and T cell-stimulating moieties. Upon peritumoral injection, the MP@RHM nanovaccine targets both the tumor site for focused chemodynamic therapy and the lymph nodes for robust tumor-specific T cell priming, thereby achieving highly efficient chemodynamic immunotherapy. Moreover, as a preventive cancer nanovaccine, MP@RHM generates strong immunological memory to inhibit postoperative tumor metastasis and recurrence. Our study findings highlight a promising approach to construct a multifunctional biomimetic nanovaccine for personalized chemodynamic immunotherapy against solid tumors.

Synthesis and characterization of 3-in-1 multifunctional lipiodol-doped Fe3O4@Poly (diallyl isophthalate) microspheres for arterial embolization, chemotherapy, and imaging.

Transcatheter arterial embolization plays a pivotal role in treating various diseases. However, the efficacy of embolization therapy in cancer treatment can be limited by several factors, such as inevitable incomplete or non-target embolization, and the tumor recurrence and metastasis caused by the hypoxic microenvironment. Moreover, it is essential to explore simpler, more economical, and efficient methods for microsphere synthesis. Herein, we achieved one-step photocatalytic synthesis of lipiodol-doped Fe3O4@Poly (diallyliso-phthalate) multifunctional microspheres (IFeD MS) for arterial embolization, chemotherapy, and imaging. The prepared microspheres are in the shape of dried plums, with a particle size of 100-300 µm. Lipiodol demonstrates a certain degree of chemotherapeutic activity, and the incorporation of Fe3O4enables the microspheres to exhibit magnetothermal response and magnetic resonance imaging capabilities. Furthermore, the radiopaque characteristics of both agents provide the microspheres with promising potential for computed tomography and digital radiography imaging. The renal embolization experiment in rabbits demonstrated that IFeD MS achieved significant embolization and chemotherapeutic effects. Biocompatibility experiments revealed that this embolic agent did not induce tissue damage or inflammation beyond the treatment area. Additionally, IFeD MS exhibited promising imaging potential. The results of this study imply that the developed multifunctional embolic agent IFeD MS may have significant potential in transforming tumors previously only suitable for palliative cares into resectable radical treatments.

Intratumoral Lactate Depletion Based on Injectable Nanoparticles-Hydrogel Composite System Synergizes with Immunotherapy against Postablative Hepatocellular Carcinoma Recurrence.

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.

Lenvatinib plus drug-eluting bead transarterial chemoembolization with/without hepatic arterial infusion chemotherapy for hepatocellular carcinoma larger than 7 cm with major portal vein tumor thrombosis: a multicenter retrospective cohort study.

BACKGROUND: The management of hepatocellular carcinoma (HCC) with high tumor burden and major portal vein tumor thrombosis (PVTT) remains a great challenge. We aimed to investigate the efficacy and safety of lenvatinib plus drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (Len+DEB-TACE+HAIC) versus lenvatinib plus DEB-TACE (Len+DEB-TACE) for HCC > 7.0 cm accompanied with major PVTT. MATERIALS AND METHODS: This multicenter retrospective cohort study evaluated consecutive patients with HCC (> 7.0 cm) and major PVTT who received Len+DEB-TACE+HAIC (Len+DEB-TACE+HAIC group) or Len+DEB-TACE (Len+DEB-TACE group) between July 2019 and June 2021 from eight institutions in China. Objective response rate (ORR), time to progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups by propensity score-matching (PSM). RESULTS: A total of 205 patients were included. After PSM, 85-paired patients remained in the study cohorts. Patients in the Len+DEB-TACE+HAIC group had higher ORR (61.2% vs. 34.1%, P < 0.001), longer TTP (median, 9.8 vs. 5.9 months, P < 0.001), and prolonged OS (median, 16.7 vs. 12.5 months, P < 0.001) than those in the Len+DEB-TACE group. The ORR and TTP of both intrahepatic tumor (ORR: 64.7% vs. 36.5%, P < 0.001; median TTP: 10.7 vs. 7.0 months, P < 0.001) and PVTT (ORR: 74.1% vs. 47.1%, P < 0.001; median TTP: 17.4 vs. 7.6 months, P < 0.001) were better in the Len+DEB-TACE+HAIC group than the Len+DEB-TACE group. The frequency of grade 3-4 TRAEs in the Len+DEB-TACE+HAIC group were comparable to those in the Len+DEB-TACE group (38.8% vs. 34.1%, P = 0.524). CONCLUSION: The addition of HAIC to Len+DEB-TACE significantly improved ORR, TTP, and OS over Len+DEB-TACE with an acceptable safety profile for large HCC with major PVTT.

Mechanisms and therapeutic strategies to combat the recurrence and progression of hepatocellular carcinoma after thermal ablation.

Thermal ablation (TA), including radiofrequency ablation (RFA) and microwave ablation (MWA), has become the main treatment for early-stage hepatocellular carcinoma (HCC) due to advantages such as safety and minimal invasiveness. However, HCC is prone to local recurrence, with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition (EMT) and remodeling of the tumor microenvironment (TME). According to many studies, various components of the TME undergo complex changes after TA, such as the recruitment of innate and adaptive immune cells, the release of tumor-associated antigens (TAAs) and various cytokines, the formation of a hypoxic microenvironment, and tumor angiogenesis. Changes in the TME after TA can partly enhance the anti-tumor immune response; however, this response is weak to kill the tumor completely. Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions, leading to tumor recurrence and progression. How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear. Thus, in this review, we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.

Nanodrug removes physical barrier to promote T-cell infiltration for enhanced cancer immunotherapy.

The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors.

Nanodrug enhances post-ablation immunotherapy of hepatocellular carcinoma via promoting dendritic cell maturation and antigen presentation.

Thermal ablation (TA) as an effective method treating hepatocellular carcinoma (HCC) in clinics is facing great challenges of high recurrence and metastasis. Although immune-checkpoint blockade (ICB)-based immunotherapy has shown potential to inhibit recurrence and metastasis, the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments. The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells (TIDCs) which leads to an inferior immune response to distant tumor growth and metastasis. Herein, an antigen-capturing nanoplatform, whose surface was modified with mannose as a targeting ligand, was constructed for co-delivering tumor-associated antigens (TAAs) and m6A demethylases inhibitor (i.e., fat mass and obesity associated gene (FTO) inhibitor) into TIDCs. In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells (DCs) maturation, improves tumor infiltration of effector T cells and generates immune memory, which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis. Therefore, the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation.

BACKGROUND: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape. METHODS: We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance. RESULTS: Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies. CONCLUSIONS: HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.

Tyrosine-kinase inhibitor combined with iodine-125 seed brachytherapy for hepatocellular carcinoma refractory to transarterial chemoembolization: a propensity-matched study.

PURPOSE: To investigate the efficacy and safety of tyrosine-kinase inhibitor (TKI) combined with iodine-125 seed brachytherapy (TKI-I) versus TKI alone for patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). METHODS: Data of patients with TACE-refractory HCC who received TKI (sorafenib or lenvatinib) or TKI-I from September 2018 to December 2020 were retrospectively analyzed. A propensity score matching (PSM) was performed to diminish potential bias. The primary endpoints were overall survival (OS) and time to progression (TTP). Tumor responses and treatment-related adverse events (TRAEs) were also compared between the two groups. RESULTS: A total of 132 patients were included in this study. Under PSM, 48 paired patients were selected for comparison. The median OS was 23.2 (95% CI 20.9-25.1) months in the TKI-I group versus 13.9 (95% CI 11.1-16.7) months in the TKI group (P < 0.001). The median TTP was 12.8 (95% CI 10.1-15.5) months in the TKI-I group versus 5.8 (95% CI 5.0-6.6) months in the TKI group (P < 0.001). Patients in the TKI-I group had higher objective response rate (68.8% vs. 33.3%, P = 0.001) and disease control rate (89.6% vs. 66.7%, P = 0.007) than those in the TKI group. The incidence and severity of TRAEs in the TKI-I group were comparable to those in the TKI group (any grade, 89.7% vs. 92.2%, P = 0.620; ≥grade 3, 33.8% vs. 32.8%, P = 0.902). CONCLUSIONS: TKI-I was safe and significantly improved survival over TKI alone in HCC patients with TACE refractoriness.

T cell-mediated targeted delivery of tadalafil regulates immunosuppression and polyamine metabolism to overcome immune checkpoint blockade resistance in hepatocellular carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed. METHODS: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed. RESULTS: TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC. CONCLUSIONS: Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.

Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.

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-ß1/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.

Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-ß1 axis in hepatocellular carcinoma.

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-ß1 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-ß1 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-ß1 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-ß1. In conclusion, IFN-γ induced TGF-ß1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-ß1 axis. Serum TGF-ß1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.

Regorafenib Combined with PD-1 Blockade Immunotherapy versus Regorafenib as Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Study.

Purpose: To evaluate the safety and efficacy of regorafenib combined with anti-PD-1 antibody sintilimab (rego-sintilimab) as a second-line treatment for advanced hepatocellular carcinoma (HCC). Methods: This multicenter retrospective study evaluated consecutive patients with advanced HCC who received rego-sintilimab (rego-sintilimab group) or regorafenib alone (regorafenib group) as a second-line treatment from January 2019 to December 2020. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Uni- and multi-variable analyses of prognostic factors for OS and PFS were performed using Cox proportional hazard regression models. Results: In total, 113 patients were included in the study: 58 received rego-sintilimab and 55 received regorafenib. The rego-sintilimab group had higher ORR (36.2% vs 16.4%, P = 0.017), longer PFS (median 5.6 vs 4.0 months; P = 0.045), and better OS (median 13.4 vs 9.9 months; P = 0.023) than the regorafenib group. Regorafenib alone, Child-Pugh B, and neutrophil-to-lymphocyte ratio (NLR) > 3.6 were independent prognostic factors for poor OS. Regorafenib alone, α-fetoprotein level, and NLR > 3.6 were independent prognostic factors for poor PFS. Subgroup analyses showed a survival benefit of rego-sintilimab in patients with NLR ≤ 3.6 (hazard ratio 0.518 [95% CI, 0.257-0.955]) but not in those with NLR > 3.6 (0.852 [0.461-1.572]); P = 0.002 for interaction. The difference in incidence of grade 3/4 adverse events between the two groups was not statistically significant (39.7% vs 30.9%; P = 0.331). Conclusion: Rego-sintilimab was tolerated and led to better OS than regorafenib as a second-line treatment for advanced HCC patients, especially in those with NLR ≤ 3.6.

Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study.

Purpose: To investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE-L-P) versus TACE combined with lenvatinib (TACE-L) for patients with advanced hepatocellular carcinoma (HCC). Materials and Methods: Data of advanced HCC patients treated with TACE-L-P (TACE-L-P group) or TACE-L (TACE-L group) from January 2019 to December 2020 were prospectively collected and retrospectively analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were determined. Results: A total of 81 patients were included in this study. Among them, 41 received TACE-L-P and 40 received TACE-L. The patients in TACE-L-P group had prolonged OS (median, 16.9 vs. 12.1 months, P=0.009), longer PFS (median, 7.3 vs. 4.0 months, P=0.002) and higher objective response rate (56.1% vs. 32.5%, P=0.033) and disease control rate (85.4% vs. 62.5%, P=0.019) than those in TACE-L group. Multivariate analyses revealed that the treatment option of TACE-L, main portal vein invasion and extrahepatic metastasis were the independent risk factors for OS, while TACE-L and extrahepatic metastasis were the independent risk factors for PFS. In subgroup analyses, a superior survival benefit was achieved with TACE-L-P in patients with extrahepatic metastasis or tumor number >3 but not in those with main portal vein invasion. The incidence and severity of AEs in TACE-L-P group were comparable to those in TACE-L group (any grade, 92.7% vs. 95.0%, P=1.000; grade 3, 36.6% vs. 32.5%, P=0.699). Conclusion: TACE-L-P significantly improved survival over TACE-L with an acceptable safety profile in advanced HCC patients, especially those with extrahepatic metastasis or tumor number >3 but without main portal vein invasion.