Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner.

BACKGROUND: Enhancing the response rate of immunotherapy will aid in the success of cancer treatment. Here, we aimed to explore the combined effect of immunogenic radiotherapy with anti-PD-L1 treatment in immunotherapy-resistant HNSCC mouse models. METHODS: The SCC7 and 4MOSC2 cell lines were irradiated in vitro. SCC7-bearing mice were treated with hypofractionated or single-dose radiotherapy followed by anti-PD-L1 therapy. The myeloid-derived suppressive cells (MDSCs) were depleted using an anti-Gr-1 antibody. Human samples were collected to evaluate the immune cell populations and ICD markers. RESULTS: Irradiation increased the release of immunogenic cell death (ICD) markers (calreticulin, HMGB1 and ATP) in SCC7 and 4MOSC2 in a dose-dependent manner. The supernatant from irradiated cells upregulated the expression of PD-L1 in MDSCs. Mice treated with hypofractionated but not single-dose radiotherapy were resistant to tumour rechallenge by triggering ICD, when combined with anti-PD-L1 treatment. The therapeutic efficacy of combination treatment partially relies on MDSCs. The high expression of ICD markers was associated with activation of adaptive immune responses and a positive prognosis in HNSCC patients. CONCLUSION: These results present a translatable method to substantially improve the antitumor immune response by combining PD-L1 blockade with immunogenic hypofractionated radiotherapy in HNSCC.

Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy.

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy.

Current cancer immunotherapy has limited response rates in a large variety of solid tumors partly due to the low immunogenicity of the tumor cells and the immunosuppressive tumor microenvironment (ITM). A number of clinical cancer treatment modalities, including radiotherapy, chemotherapy, photothermal and photodynamic therapy, have been shown to elicit immunogenicity by inducing immunogenic cell death (ICD). However, ICD-based immunotherapy is restricted by the ITM limiting its efficacy in eliciting a long-term antitumor immune response, and by severe systemic toxicity. To address these challenges, nanomedicine-based drug delivery strategies have been exploited for improving cancer immunotherapy by boosting ICD of the tumor cells. Nanosized drug delivery systems are promising for increasing drug accumulation at the tumor site and codelivering ICD inducers and immune inhibitors to simultaneously elicit the immune response and relieve the ITM. This review highlights the recent advances in nanomedicine-based immunotherapy utilizing ICD-based approaches. A perspective on the clinical translation of nanomedicine-based cancer immunotherapy is also provided.

Cancer nanomedicine meets immunotherapy: opportunities and challenges.

Cancer nanomedicines have shown promise in combination immunotherapy, thus far mostly preclinically but also already in clinical trials. Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. Combination nano-immunotherapy can be realized via three targeting strategies, i.e., by targeting cancer cells, targeting the tumor immune microenvironment, and targeting the peripheral immune system. The clinical potential of nano-immunotherapy has recently been demonstrated in a phase III trial in which nano-albumin paclitaxel (Abraxane®) was combined with atezolizumab (Tecentriq®) for the treatment of patients suffering from advanced triple-negative breast cancer. In the present paper, besides strategies and initial (pre)clinical success stories, we also discuss several key challenges in nano-immunotherapy. Taken together, nanomedicines combined with immunotherapy are gaining significant attention, and it is anticipated that they will play an increasingly important role in clinical cancer therapy.

Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy.

The clinical performance of conventional cancer therapy approaches (surgery, radiotherapy, and chemotherapy) has been challenged by tumor metastasis and recurrence that is mainly responsible for cancer-caused mortalities. The cancer immunotherapy is being emerged nowadays as a promising therapeutic modality in order to achieve a highly efficient therapeutic performance while circumventing tumor metastasis and relapse. Liposomal nanoparticles (NPs) may serve as an ideal platform for systemic delivery of the immune modulators. In this review, we summarize the cutting-edge progresses in liposomal NPs for cancer immunotherapy, with focus on dendritic cells, T cells, tumor cells, natural killer cells, and macrophages. The review highlights the major challenges and provides a perspective regarding the clinical translation of liposomal nanoparticle-based immunotherapy.

Anticancer activity of Astragalus polysaccharide in human non-small cell lung cancer cells.

BACKGROUND: We have reported that Chinese herbs Astragalus polysaccharide (APS) can inhibit nuclear factor kappaB (NF-κB) activity during the development of diabetic nephropathy in mice. NF-κB plays important roles in genesis, growth, development and metastasis of cancer. NF-κB is also involved in the development of treatment resistance in tumors. Here we investigated the antitumor activity of APS in human non-small cell lung cells (A549 and NCI-H358) and the related mechanisms of action. METHODS: The dose-effect and time-effect of antitumor of APS were determined in human lung cancer cell line A549 and NCI-H358. The inhibition effect of APS on the P65 mRNA and protein was detected by reverse transcriptase-PCR (RT-PCR) and Western blot in A549 cells respectively. The inhibition effect of APS on the p50, CyclinD1 and Bcl-xL protein was detected by Western blot in A549 cells respectively. The effect of APS on NF-κB transcription activity was measured with NF-κB luciferase detection. Finally, the nude mice A549 xenograft was introduced to confirm the antitumor activity of APS in vivo. RESULTS: Cell viability detection results indicated that APS can inhibit the proliferation of human lung cancer cell line A549 and NCI-H358 in the concentration of 20 and 40 mg/mL. NF-κB activator Phorbol 12-myristate13-acetate (PMA) can attenuate the antitumor activity of APS in both cell lines, but NF-κB inhibitor BAY 11-7082 (Bay) can enhance the effect of APS in both cell lines. In vivo APS can delay the growth of A549 xenograft in BALB/C nude mice. APS can down-regulate the expression of P65 mRNA and protein of A549 cells and decrease the expression of p50, CyclinD1 and Bcl-xL protein. The luciferase detection showed that the APS could reduce the P65 transcription activity in A549 cells. PMA can partially alleviate the inhibition activity of P65 transcription activity of APS in A549 cells, and Bay can enhance the down-regulation of the P65 transcription activity induced by APS in A549 cells. CONCLUSION: APS has a significant antitumor activity in human lung cancer cells A549 and NCI-H358. NF-κB inhibition may mediate the antitumor effect.

Smart nanoparticles improve therapy for drug-resistant tumors by overcoming pathophysiological barriers.

The therapeutic outcome of chemotherapy is severely limited by intrinsic or acquired drug resistance, the most common causes of chemotherapy failure. In the past few decades, advancements in nanotechnology have provided alternative strategies for combating tumor drug resistance. Drug-loaded nanoparticles (NPs) have several advantages over the free drug forms, including reduced cytotoxicity, prolonged circulation in the blood and increased accumulation in tumors. Currently, however, nanoparticulate drugs have only marginally improved the overall survival rate in clinical trials because of the various pathophysiological barriers that exist in the tumor microenvironment, such as intratumoral distribution, penetration and intracellular trafficking, etc. Smart NPs with stimulus-adaptable physico-chemical properties have been extensively developed to improve the therapeutic efficacy of nanomedicine. In this review, we summarize the recent advances of employing smart NPs to treat the drug-resistant tumors by overcoming the pathophysiological barriers in the tumor microenvironment.

Silibinin and indocyanine green-loaded nanoparticles inhibit the growth and metastasis of mammalian breast cancer cells in vitro.

AIM: To improve the therapeutic efficacy of cancer treatments, combinational therapies based on nanosized drug delivery system (NDDS) has been developed recently. In this study we designed a new NDDS loaded with an anti-metastatic drug silibinin and a photothermal agent indocyanine green (ICG), and investigated its effects on the growth and metastasis of breast cancer cells in vitro. METHODS: Silibinin and ICG were self-assembled into PCL lipid nanoparticles (SIPNs). Their physical characteristics including the particle size, zeta potential, morphology and in vitro drug release were examined. 4T1 mammalian breast cancer cells were used to evaluate their cellular internalization, cytotoxicity, and their influences on wound healing, in vitro cell migration and invasion. RESULTS: SIPNs showed a well-defined spherical shape with averaged size of 126.3±0.4 nm and zeta potential of -10.3±0.2 mV. NIR laser irradiation substantially increased the in vitro release of silibinin from the SIPNs (58.3% at the first 8 h, and 97.8% for the total release). Furthermore, NIR laser irradiation markedly increased the uptake of SIPNs into 4T1 cells. Under the NIR laser irradiation, both SIPNs and IPNs (PCL lipid nanoparticles loaded with ICG alone) caused dose-dependent ablation of 4T1 cells. The wound healing, migration and invasion experiments showed that SIPNs exposed to NIR laser irradiation exhibited dramatic in vitro anti-metastasis effects. CONCLUSION: SIPNs show temperature-sensitive drug release following NIR laser irradiation, which can inhibit the growth and metastasis of breast cancer cells in vitro.

Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.

A dysprosium(III)-based triple helical-like complex as a turn-on/off fluorescence sensor for Al(III) and 4,5-dimethyl-2-nitroaniline.

A novel triple helical-like complex [Dy2K2L3(NO3)2]·3DMF (1) based on a designed Schiff base N'1,N'3-bis((E)-3-ethoxy-2-hydroxybenzylidene)-malonohydrazide (H4L) was synthesized with good chemical and thermal stabilities. Single-crystal X-ray structural analysis showed that 1 presents a tetranuclear triple helical-like structure via the coordination mode of Dy : K : L with 2 : 2 : 3 stoichiometry. Fluorescence measurements showed that 1@EtOH has excellent fluorescence turn-on/off response ability for aluminium ions and 4,5-dimethyl-2-nitroaniline (DMNA) with outstanding selectivity, sensitivity, and anti-interference ability. The calculated limit of detection (LOD) values for 1@EtOH to Al3+ and DMNA were found to be 0.53 and 3.33 µM, respectively. Density functional theory (DFT) calculation showed that the fluorescence response mechanism can be explained by the photoinduced electron transfer (PET) mechanism; meanwhile, the inner filter effect (IFE) of DMNA can also affect the emission of 1@EtOH.

Tertiary lymphoid structures and cytokines interconnections: The implication in cancer immunotherapy.

Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes and antigen-presenting cells that develop in non-lymphoid tissues during chronic inflammation, resembling the structure and features of secondary lymphoid organs. Numerous studies have shown that TLSs may be an important source of antitumor immunity within solid tumors, facilitating T cell and B cell differentiation and the subsequent production of antitumor antibodies, which are beneficial for cancer prognosis and responses to immunotherapy. The formation of TLSs relies on the cytokine signaling network between heterogeneous cell populations, such as stromal cells, lymphocytes and cancer cells. The coordinated action of various cytokines drives the complex process of TLSs development. In this review, we will comprehensively describe the mechanisms by which various cytokines regulate TLS formation and function, and the recent advancements and therapeutic potential of exploiting these mechanisms to induce intratumoral TLSs as an emerging immunotherapeutic approach or to enhance existing immunotherapy.

VISTA blockade alleviates immunosuppression of MDSCs in oral squamous cell carcinoma.

V-domain Ig suppressor of T-cell activation (VISTA) is a novel immune checkpoint regulator that can inhibit T cell-mediated antitumor immunity. Although the use of anti-VISTA monoclonal antibody has demonstrated encouraging outcomes in the therapy of various malignancies, its specific impact and underlying mechanisms in oral squamous cell carcinoma (OSCC) remain to be explored. In this work, we analyzed human OSCC tissue microarrays, human peripheral blood mononuclear cells, and immunocompetent transgenic mouse models to investigate the relationship between high VISTA expression and markers of myeloid-derived immunosuppressive cells (MDSCs; CD11b, CD33, Arginase-1), tumor-associated macrophages (CD68, CD163, CD206), and T cell function (CD8, PD-L1, Granzyme B). In OSCC, we discovered that VISTA was highly expressed and stably expressed in MDSCs. Furthermore, we established a mouse OSCC orthotopic xenograft tumor model to investigate the impact of VISTA blockade on the tumor microenvironment. We found that VISTA blockade reduces the immunosuppressive microenvironment and delays tumor growth. This is achieved by suppressing the quantity and function of MDSCs while boosting the function of tumor-infiltrating T cells. Our research indicated that VISTA expressed by MDSCs has a crucial function in the progression of OSCC and that VISTA blockade therapy is a promising immune checkpoint blockade therapy.

New or little-known Boreoheptagyia (Diptera, Chironomidae) in China inferred from morphology and DNA barcodes.

The male adult of Boreoheptagyia zhengi Lin & Liu, sp. nov. is described and illustrated based on material collected in China. Associated morphological characteristics and reference to its DNA barcode are provided. Boreoheptagyia kurobebrevis (Sasa & Okazawa, 1992) is newly recorded from China based on both a male and female, with additional associated data on the DNA barcode of the male adult. A neighbor-joining tree based on available Boreoheptagyia DNA barcodes and a key to the adults of Boreoheptagyia from China are given.

Species delimitation and life stage association of Propsilocerus Kieffer, 1923 (Diptera, Chironomidae) using DNA barcodes.

The utility of COI DNA barcodes in species delimitation is explored as well as life stage associations of five closely related Propsilocerus species: Propsilocerus akamusi (Tokunaga, 1938), Propsilocerus paradoxus (Lundström, 1915), Propsilocerus saetheri Wang, Liu et Paasivirta, 2007, Propsilocerus sinicus Sæther et Wang, 1996, and Propsilocerus taihuensis (Wen, Zhou et Rong, 1994). Results revealed distinctly larger interspecific than intraspecific divergences and indicated a clear "barcode gap". In total, 42 COI barcode sequences including 16 newly generated DNA barcodes were applied to seven Barcode Index Numbers (BINs). A neighbor-joining (NJ) tree comprises five well-separated clusters representing five morphospecies. Comments on how to distinguish the larvae of P. akamusi and P. taihuensis are provided.

DNA barcodes and morphology confirm a new species of Rheocricotopus (Psilocricotopus) orientalis group (Diptera: Chironomidae).

Morphology and DNA barcodes confirm a new chironomid species within the Rheocricotopus (Psilocricotopus) orientalis group (Diptera: Chironomidae). Rheocricotopus (Psilocricotopus) kongi Lin et Wang sp. n. is described and illustrated based on adult male from Hainan, China. Key to adult males of the R. orientalis group is given.

Room-temperature reduction of NO2 in a Li-NO2 battery: a proof of concept.

Although considerable effort has been devoted to purifying nitrogen oxides (NOx), it is still challenging to effectively reduce NOx at room temperature and ambient pressure without catalysts. In this study, as a proof-of-concept, we have for the first time demonstrated the room-temperature reduction of nitrogen dioxide (NO2) using a rechargeable lithium-nitrogen dioxide (Li-NO2) battery. The battery shows a capacity of 884 mAh g-1 at 50 mA g-1 (an actual energy density of 666 Wh kg-1) and a promising electrochemical Faraday efficiency (FE) of 67%. The unique properties of Li-NO2 rechargeable batteries not only provide a way to reduce and recycle NO2 but also highlight the potential of oxidative air pollutants as energy sources for next-generation electrochemical energy storage (EES) systems.

Increased expression of telomere-related proteins correlates with resistance to radiation in human laryngeal cancer cell lines.

Telomere-associated proteins function as survival factors in telomere maintenance, which are major contributors to radiosensitivity in human cancers. The aim of this study was to investigate the association of telomere-associated gene expression and radiation resistance in human larynx squamous carcinoma. The changes of telomere-associated gene expressions and bionomical characteristics that occur in two human larynx squamous carcinoma cell lines (Hep-2 and Hep-2R), with different radiosensitivities in vitro were explored in the present study. Based on previous research, elevated POT1 and TPP1 expressions were detected by reverse transcription-PCR and Western blotting in Hep-2R cell lines. Furthermore, Hep-2R cells showed increased recovery ratio accompanied by a reduction of cell arrested in G2/S phase, suggesting that the radioresistance of Hep-2R cells was due to a faster growth in which telomere length had recently been demonstrated to be a powerful prognostic marker. These results manifest that radioresistant Hep-2R cell lines showed certain changes in gene expression and bionomical profiles that are different from the profile changes of the more-sensitive Hep-2 cell lines, and that evaluation of telomere-associated genes may be a prognostic marker for response to radiotherapy in larynx squamous cell carcinoma (LSCC).