Homologous-magnetic dual-targeted metal-organic framework to improve the Anti-hepatocellular carcinoma efficacy of PD-1 inhibitor.

The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone IIA (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal-organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.

Formation of pre-metastatic niches induced by tumor extracellular vesicles in lung metastasis.

There are a number of malignant tumors that metastasize into the lung as one of their most common sites of dissemination. The successful infiltration of tumor cells into distant organs is the result of the cooperation between tumor cells and distant host cells. When tumor cells have not yet reached distant organs, in situ tumor cells secrete extracellular vesicles (EVs) carrying important biological information. In recent years, scholars have found that tumor cells-derived EVs act as the bridge between orthotopic tumors and secondary metastases by promoting the formation of a pre-metastatic niche (PMN), which plays a key role in awakening dormant circulating tumor cells and promoting tumor cell colonization. This review provides an overview of multiple routes and mechanisms underlying PMN formation induced by EVs and summaries study findings that underline a potential role of EVs in the intervention of lung PMN, both as a target or a carrier for drug design. In this review, the underlying mechanisms of EVs in lung PMN formation are highlighted as well as potential applications to lung metastasis diagnosis and treatment.

[Preparation of two tanshinone â ¡_A-astragaloside â £ co-loaded nano-delivery systems and in vitro antitumor activity comparison].

This study screened excellent carriers for co-loading tanshinone Ⅱ_A(TSA) and astragaloside Ⅳ(As) to construct antitumor nano-drug delivery systems for TSA and As. TSA-As microemulsions(TSA-As-MEs) were prepared by water titration. TSA-As metal-organic framework(MOF) nano-delivery system was prepared by loading TSA and As in MOF by the hydrothermal method. Dynamic light scattering(DLS), transmission electron microscopy(TEM), and scanning electron microscopy(SEM) were used to characterize the physicochemical properties of the two preparations. Drug loading was determined by HPLC and the effects of the two preparations on the proliferation of vascular endothelial cells, T lymphocytes, and hepatocellular carcinoma cells were detected by the CCK-8 method. The results showed that the particle size, Zeta potential, and drug loading of TSA-As-MEs were(47.69±0.71) nm,(-14.70±0.49) mV, and(0.22±0.01)%, while those of TSA-As-MOF were(258.3±25.2) nm,(-42.30 ± 1.27) mV, and 15.35%±0.01%. TSA-As-MOF was superior to TSA-As-MEs in drug loading, which could inhibit the proliferation of bEnd.3 cells at a lower concentration and improve the proliferation ability of CTLL-2 cells significantly. Therefore, MOF was preferred as an excellent carrier for TSA and As co-loading.

Icaritin ameliorates extracellular microparticles-induced inflammatory pre-metastatic niche via modulating the cGAS-STING signaling.

The concept of the inflammatory pre-metastatic niche (PMN) provides a new and promising direction for the prevention and treatment of metastasis. The excessive activation of the GAS-STING signaling leads to augmented metastasis by promoting the formation of the inflammatory PMN. In this study, tumor-derived microparticles (MP) were used to establish the PMN model both in vitro and in vivo, and pro-inflammatory mediators were also employed to evaluate the effects of Icaritin (ICT). It was demonstrated that ICT could inhibit the pulmonary metastasis of B16BL6 melanoma cells in mice via interfering with PMN. The phosphorylation and dimerization of STING and its downstream signaling TBK1-IFNß were proved to be diminished in the presence of ICT. Furthermore, we revealed that ICT suppressed the generation of pro-inflammatory PMN through conferring the inactivation of the STING signaling pathway. CETSA and DARTS assay also confirmed that STING tended to be a target for the action of ICT. Collectively, our findings highlight a new binding mechanism between STING and ICT for the inhibition of transduction of the STING signaling pathway, suggesting that pharmacological or therapeutic intervention of the STING-TBK1-IFNß singling axis may serve as an effective strategy to prevent the progression of inflammatory PMN and lung metastasis.

Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.

BACKGROUND: Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown. PURPOSE: The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo. METHODS: We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated. RESULTS: We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ. CONCLUSIONS: This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC.

Combination of oxymatrine (Om) and astragaloside IV (As) enhances the infiltration and function of TILs in triple-negative breast cancer (TNBC).

Triple-negative breast cancer (TNBC) is the most aggressive subtype and has a poor response to treatment due to an immunosuppressive microenvironment. Chinese Medicine effective constituents such as oxymatrine (Om) and astragaloside IV (As) have shown promise in cancer treatment by providing anti-fibrosis and immune-enhancing effects. However, the potential combined effect of Om and As on TNBC and its mechanism is still uncertain. This study focuses on exploring the impact of Om and As on enhancing the immunosuppressive microenvironment of TNBC and uncovering the potential mechanism behind it. In this study, a trans-Cancer associated fibroblasts (CAFs) infiltration system of T cells was utilized to investigate the potential benefits of Om, while the impact of As on the morphology and quantity of mitochondria in T cells was examined in a co-culture system with tumor cells. Further to investigate the combined effects of Om and As on tumor suppression and immunosuppressive microenvironment improvement, this study established an in situ TNBC mouse model with 4 T1-luc. In vitro, our findings indicate that Om can effectively suppress the activation of CAFs by downregulating the expression of FAP and α-SMA, and also promoting the infiltration of T cells trans CAFs. It was discovered that the mitochondrial activity of T cells could be improved by increasing the number of mitochondria and cristae. In vivo, the optimal ratio of Om and As (2:1) was found to increase the apoptosis rate of tumor cells in a co-culture system and enhance the infiltration of CD4+ and CD8+ T cells, as confirmed by Flow Cytometry results. Our study suggests that Om and As could enhance the immune system's ability to treat TNBC by improving the infiltration and increasing the anti-tumor function of TILs. This intervention may lead to a promising therapeutic direction for the treatment of TNBC.

Magnetic Metal-Organic Framework-Based Nanoplatform with Platelet Membrane Coating as a Synergistic Programmed Cell Death Protein 1 Inhibitor against Hepatocellular Carcinoma.

Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC). However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function. In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment. We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33.77 wt %) and good immune escape. Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs. In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84.15% and prolonged the survival time of mice. Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.