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Abstract Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms. Graphical Abstract

Hepatic stellate cells (HSCs) represent a significant component of hepatocellular carcinoma (HCC) microenvironments which play a critical role in tumor progression and drug resistance. Tumor-on-a-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal control. Here we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC progression. On-chip analysis revealed activated HSCs contributed to endothelial invasion, HCC drug resistance and natural killer (NK) cell exhaustion. Cytokine array and RNA sequencing analysis were combined to indicate the iron-binding protein LIPOCALIN-2 (LCN-2) as a key factor in remodeling tumor microenvironments in the HCC-on-a-chip. LCN-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model, including angiogenesis inhibition, sorafenib sensitivity promotion and NK-cell cytotoxicity enhancement. Taken together, the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.

Tumor cell extravasation across endothelial barrier has been recognized as a pivotal event in orchestrating metastasis formation. This event is initiated by the interactions of extravasating tumor cells with endothelial cells (ECs). Therefore, targeting the crosstalk between tumor cells and ECs might be a promising therapeutic strategy to prevent metastasis. In this study, we demonstrated that Rh1, one of the main ingredients of ginseng, hindered the invasion of breast cancer (BC) cells as well as diminished the permeability of ECs both in vitro and in vivo, which was responsible for the attenuated tumor cell extravasation across endothelium. Noteworthily, we showed that ECs were capable of inducing the epithelial-mesenchymal transition (EMT) and invadopodia of BC cells that are essential for tumor cell migration and invasion through limiting the nuclear translocation of hematopoietically expressed homeobox (HHEX). The decreased nuclear HHEX paved the way for initiating the CCL20/CCR6 signaling axis, which in turn contributed to damaged endothelial junctions, uncovering a new crosstalk mode between tumor cells and ECs. Intriguingly, Rh1 inhibited the kinase activity of casein kinase II subunit alpha (CK2α) and further promoted the nuclear translocation of HHEX in the BC cells, which resulted in the disrupted crosstalk between chemokine (C-C motif) ligand 20 (CCL20) in the BC cells and chemokine (C-C motif) receptor 6 (CCR6) in the ECs. The prohibited CCL20-CCR6 axis by Rh1 enhanced vascular integrity and diminished tumor cell motility. Taken together, our data suggest that Rh1 serves as an effective natural CK2α inhibitor that can be further optimized to be a therapeutic agent for reducing tumor cell extravasation.

Abstract Cancer treatment by inducing tumor cell immunogenic cell death (ICD) is critical for tumor therapy. However, ICD activation by single pathway is often limited in practical application due to its low efficiency. In addition, the low pH and anoxic microenvironments in solid tumors greatly limit the effective activation of ICD. Herein, hollow manganese dioxide (H-MnO2) nanomaterials were selected to load both Mitoxantrone (MTZ) and Chlorin e6 (Ce6) due to its hollow structure and ability to release drugs in the acidic environments. Thus, the synergy of photodynamic therapy (PDT), photothermal therapy (PTT) and chemotherapy can induce the process of immunogenic cell death, stimulate the maturation of dendritic cells (DCs), and activate the immune response to kill tumor cells dramatically. Efficient immunotherapeutic effects were obtained when MnO2-C/M-HA was given intravenously to 4T1 tumor-bearing BALB/c mice with 660 nm near-infrared laser irradiation. This study overcame the limitations of monotherapy and provided a multifunctional platform for tumor immunotherapy.

Calcium sulfoaluminate (CSA) cement, as a type of low-carbon cement, can contribute to further reduction in carbon emissions with carbonation technologies. However, the detailed microstructure development of CSA cement during the carbonation process has been rarely analyzed. In this paper, wet carbonation was applied to CSA cement to investigate the microstructure evolution of carbonation products and carbon absorption capacity of CSA cement by means of pH measurement, X-ray diffraction (XRD) measurement, thermogravimetric (TG) measurement, Fourier-transformed infrared spectroscopy (FT-IR) measurement and scanning electron microscope measurement. During the carbonation process, the formed ettringite product and the dicalcium silicate clinker were carbonated immediately to generate calcium carbonate crystals, silica gel and aluminum hydroxide (AH3) gel. With the trend of pH increasing first and notably decreasing later, the coupling interaction between the hydration and carbonation reactions of CSA cement was revealed. From the XRD and TG results, three types of calcium carbonate crystal forms (calcite, vaterite and aragonite) were detected, and the content of calcium carbonate increased with the increase in carbonation time. FT-IR analysis further confirmed the existence of calcium carbonate, silica gel and AH3 gel with their characteristic vibrations. Moreover, the microstructure of carbonation products with different morphologies was observed. The application of wet carbonation to CSA cement provides a more comprehensive insight to the carbonation mechanism of this low-carbon cement.

Immunotherapy has been recognized as an effective and important therapeutic modality for multiple types of cancer. Nevertheless, it has been increasing recognized that clinical benefits of immunotherapy are less than expected as evidenced by the fact that only a small population of cancer patients respond favorably to immunotherapy. The structurally and functionally abnormal tumor vasculature is a hallmark of most solid tumors and contributes to an immunosuppressive microenvironment, which poses a major challenge to immunotherapy. In turn, multiple immune cell subsets have profound consequences on promoting neovascularization. Vascular normalization, a promising anti-angiogenic strategy, can enhance vascular perfusion and promote the infiltration of immune effector cells into tumors via correcting aberrant tumor blood vessels, resulting in the potentiation of immunotherapy. More interestingly, immunotherapies are prone to boost the efficacy of various anti-angiogenic therapies and/or promote the morphological and functional alterations in tumor vasculature. Therefore, immune reprograming and vascular normalization appear to be reciprocally regulated. In this review, we mainly summarize how tumor vasculature propels an immunosuppressive phenotype and how innate and adaptive immune cells modulate angiogenesis during tumor progression. We further highlight recent advances of anti-angiogenic immunotherapies in preclinical and clinical settings to solidify the concept that targeting both tumor blood vessels and immune suppressive cells provides an efficacious approach for the treatment of cancer.

Abstract Background It is well accepted that the immune system efficiently contributes to positive outcomes of chemotherapeutic cancer treatment by activating immunogenic cell death (ICD). However, only a limited number of ICD-inducing compounds are well characterized at present; therefore, identification of novel ICD inducers is urgently needed for cancer drug discovery, and the need is becoming increasingly urgent. Methods Herein, we assessed the antitumour activity of bullatacin by MTS assay and apoptosis assay. ICD biomarkers, such as calreticulin (CRT), high-mobility group protein B1 (HMGB-1), heat shock protein (HSP)70, HSP90 and ATP, were assessed by Western blotting, ELISA and flow cytometry. Western blot and qPCR assays were performed to explore the underlying mechanisms of bullatacin-induced ICD. Flow cytometry was used to detect macrophage phagocytosis. Results First, bullatacin induced apoptosis in both SW480 cells and HT-29 cells in a time-dependent manner at 10 nM, as assessed by flow cytometry. Moreover, Western blot and flow cytometry assays showed that CRT and HSP90 (biomarkers of early ICD) significantly accumulated on the cell membrane surface after approximately 6 h of treatment with bullatacin. In addition, ELISAs and Western blot assays showed that the second set of hallmarks required for ICD (HMGB1, HSP70 and HSP90) were released in the conditioned media of both SW480 and HT-29 cells after 36 h of treatment. Furthermore, qPCR and Western blot assays indicated that bullatacin triggered ICD via activation of the endoplasmic reticulum stress (ERS) signalling pathway. Finally, bullatacin promoted macrophage phagocytosis. Conclusion This study documents that bullatacin, a novel ICD inducer, triggers immunogenic tumour cell death by activating ERS even at a relatively low concentration in vitro.

The inferior mechanical properties and durability of conventional lightweight concrete restrict its wider application. This study intended to design a novel lightweight ultra high-performance concrete (L-UHPC) using a mathematical approach, with a view to achieving low density and excellent performance. Two lightweight materials (i.e. micro-sized glass microsphere and expanded shale aggregates) were introduced in the mix design of L-UHPC. The statistical optimization via Central Composite Design was proved to be an effective method to produce the L-UHPC. The designed L-UHPC showed comparable or even superior functional and durability properties than normal-weight UHPC and high-performance cement mortar. The use of specified lightweight materials played prominent roles in ensuring the mechanical properties of L-UHPC. The high microhardness of paste matrix and the internal curing of lightweight aggregates contributed to the great durability of L-UHPC. The development of L-UHPC can provide a new solution for constructing high-performance lightweight structures and composites.

The role of gut microbiota in the development of various tumors has been a rising topic of public interest, and in recent years, many studies have reported a close relationship between microbial groups and tumor development. Gut microbiota play a role in host metabolism, and the positive and negative alterations of these microbiota have an effect on tumor treatment. The microbiota directly promote, eliminate, and coordinate the efficacy of chemotherapy drugs and the toxicity of adjuvant drugs, and enhance the ability of patients to respond to tumors in adjuvant immunotherapy. In this review, we outline the significance of gut microbiota in tumor development, reveal its impacts on chemotherapy and immunotherapy, and discover various potential mechanisms whereby they influence tumor treatment. This review demonstrates the importance of intestinal microbiota-related research for clinical tumor treatment and provides additional strategy for clinical assistance in cancer treatment.

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.