Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

The direct antitumor effect of bevacizumab (BEV) has long been debated. Evidence of the direct antitumor activities of drugs are mainly obtained from in vitro experiments, which are greatly affected by experimental conditions. In this study, we evaluated the effect of BEV-containing medium renewal on the results of in vitro cytotoxicity experiments in A549 and U251 cancer cells. We observed starkly different results between the experiments with and without BEV-containing medium renewal. Specifically, BEV inhibited the tumor cell growth in the timely replacement with a BEV-containing medium but promoted tumor cell growth without medium renewal. Meanwhile, compared with the control, a significant basic fibroblast growth factor (bFGF) accumulation in the supernatant was observed in the group without medium renewal but none in that with replaced medium. Furthermore, bFGF neutralization partially reversed the pro-proliferative effect of BEV in the medium non-renewed group, while exogenous bFGF attenuated the tumor cell growth inhibition of BEV in the medium-renewed group. Our data explain the controversy over the direct antitumor effect of BEV in different studies from the perspective of the compensatory autocrine cytokines in tumor cells.

B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with adverse clinical outcomes. In addition to its well-known immune functions, B7-H3 exhibits dual co-stimulatory/co-inhibitory roles in normal physiology and the tumor microenvironment. The non-immune functions of B7-H3 in tumor cells and the tumor vasculature, including promoting tumor cell anti-apoptosis, proliferation, invasion, migration, drug resistance, radioresistance, as well as affecting cellular metabolism and angiogenesis, have increasingly gained attention from researchers. Particularly, the co-expression of B7-H3 in both tumor cells and tumor endothelial cells highlights the higher potential and clinical utility of therapeutic strategies targeting B7-H3. This review aims to summarize the recent advances in understanding the non-immune functions of B7-H3 in tumors and provide insights into therapeutic approaches targeting B7-H3, focusing on its co-expression in tumor cells and endothelial cells. The aim is to establish a theoretical foundation and practical reference for the development and optimization of B7-H3-targeted therapies.

Tumor-specific fluorescent probes must fulfill the dual requirements of targeted accumulation within tumors and high-resolution imaging capabilities. To achieve both tumor-targeted accumulation and high-resolution imaging performance, we developed a composite comprising an acid-responsive bodipy conjugated to amphiphilic PEG-b-PLA polymer, along with folic acid (FA)-modified PEG-b-PLA as a targeting moiety for active tumor-specific accumulation. Finally, a novel assembly of hybrid fluorescent nanoparticles was successfully synthesized by integrating these two components, demonstrating exceptional responsiveness to acidic conditions for fluorescence excitation and remarkable tumor-targeted accumulation capabilities. We conducted comprehensive in vitro and in vivo investigations employing techniques such as analysis of physicochemical properties, fluorescence-based probes detection at varying pH levels, assessment of in vitro cytotoxicity, evaluation of cellular uptake capacity, analysis of lysosomal co-localization imaging, examination of tumor fluorescence images in vivo, and investigation of biological distribution patterns. The results demonstrated that the acid-responsive nanofluorescence probe we designed and synthesized possesses desirable physical and chemical characteristics, including a small particle size and low cytotoxicity. Moreover, it exhibits rapid real-time response to acidic environments and displays enhanced fluorescence intensity, enabling the real-time tracking of probe entry into tumor cells as well as intracellular lysozyme accumulation. We achieved highly specific in vivo tumor visualization by combining nanoprobes targeting folate receptor. Through imaging cervical tumor mice, we demonstrated the precise imaging performance and high targeted accumulation of FA-targeted nanofluorescence probes in tumor tissue. Furthermore, we confirmed the in vivo safety of the FA-targeted nanofluorescence probe through biological distribution analysis. These findings highlight the potential widespread application of FA-targeted acid-responsive nanofluorescence probes for selective imaging of tumor cells and tissues.

Branched-chain amino acids (BCAAs), including leucine, valine, and isoleucine, play crucial roles in regulating metabolic balance and maintaining physiological functions in the body. Extensive studies have been focused on their implications in obesity, diabetes, and cardiovascular diseases. Nevertheless, accumulating evidence suggests that BCAAs metabolism also plays significant roles in tumorigenesis and progression. In this review, we overview recent progress of the study on BCAAs metabolism including its relationship with epigenetic regulation. Particularly, we discuss the metabolic reprogramming and metabolic sensing of BCAAs and its intermediate metabolites in tumor cells and microenvironment to decipher their functions. An enhanced understanding of the roles and mechanism of BCAAs metabolism in tumorigenesis and progression will contribute to development of novel therapeutic strategies against tumor.
支链氨基酸(branched-chain amino acids，BCAAs)，包括亮氨酸、缬氨酸和异亮氨酸，在调节体内代谢平衡、维持正常生命活动中发挥着重要作用。许多研究报道了它们在肥胖、糖尿病和心血管等疾病中的代谢和功能。近些年研究表明，BCAAs代谢在肿瘤发生发展中也起着重要作用。本文综述了BCAAs代谢在该方面的研究进展，包括与表观遗传调控的关系，特别是围绕肿瘤代谢重塑和代谢感知，讨论了其在肿瘤细胞和肿瘤微环境(tumor microenvironment，TME)中的作用。深入了解BCAAs代谢在肿瘤发生发展中的作用及其机制有助于为开发新的肿瘤治疗策略提供理论基础。.

Single-cell sequencing has revolutionized our ability to dissect the heterogeneity within tumor populations. In this study, we present LoRA-TV (Low Rank Approximation with Total Variation), a novel method for clustering tumor cells based on the read depth profiles derived from single-cell sequencing data. Traditional analysis pipelines process read depth profiles of each cell individually. By aggregating shared genomic signatures distributed among individual cells using low-rank optimization and robust smoothing, the proposed method enhances clustering performance. Results from analyses of both simulated and real data demonstrate its effectiveness compared with state-of-the-art alternatives, as supported by improvements in the adjusted Rand index and computational efficiency.

Efficient protection and precise delivery of biomolecules are of critical importance in the intervention and therapy of various diseases. Although diverse specific marker-functionalized drug carriers have been developed rapidly, current approaches still encounter substantial challenges, including strong immunogenicity, limited target availability, and potential side effects. Herein, we developed a biomimetic exosome-sheathed magnetic mesoporous anchor modified with glucose oxidase (MNPs@mSiO2-GOx@EM) to address these challenges and achieve synergistic targeting and starving of tumor cells. The MNPs@mSiO2-GOx@EM anchor integrated the unique characteristics of different components. An external decoration of exosome membrane (EM) with high biocompatibility contributed to increased phagocytosis prevention, prolonged circulation, and enhanced recognition and cellular uptake of loaded particles. An internal coated magnetic mesoporous core with rapid responsiveness by the magnetic field guidance and large surface area facilitated the enrichment of nanoparticles at the specific site and provided enough space for modification of glucose oxidase (GOx). The inclusion of GOx in the middle layer accelerated the energy-depletion process within cells, ultimately leading to the starvation and death of target cells with minimal side effects. With these merits, in vitro study manifested that our nanoplatform not only demonstrated an excellent targeting capability of 94.37% ± 1.3% toward homotypic cells but also revealed a remarkably high catalytical ability and cytotoxicity on tumor cells. Assisted by the magnetic guidance, the utilization of our anchor obviously inhibits the tumor growth in vivo. Together, our study is promising to serve as a versatile method for the highly efficient delivery of various target biomolecules to intended locations due to the fungibility of exosome membranes and provide a potential route for the recognition and starvation of tumor cells.

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Liposomes have been widely studied as drug carriers for clinical application, and the key issue is how to achieve effective delivery through targeting strategies. Even though certain cell-level targeting or EPR effect designs have been developed, reaching sufficient drug concentration in intracellular regions remains a challenge due to the singularity of functionality. Herein, benefiting from the unique features of tumor from tissue to cell, a dual-thermosensitive and dual-targeting liposome (DTSL) was creatively fabricated through fine microstructure tailoring, which holds intelligent both tissue-regulated active-to-passive binding and membrane-derived homologous-fusion (HF) properties. At the micro level, DTSL can actively capture tumor cells and accompany the enhanced HF effect stimulated by self-constriction, which achieves a synergistic promotion effect targeting tissues to cells. As a result, this first active-then passive targeting process makes drug delivery more accurate and effective, and after dynamic targeting into cells, the nucleus of DTSL undergoes further thermally responsive contraction, fully releasing internal drugs. In vivo experiments showed that liposomes with dual targeting and dual thermosensitive features almost completely inhibited tumor growth. Summarized, these results provide a reference for a rational design and microstructural tailoring of the liposomal co-delivery system of drugs, suggesting that active-to-passive dual-targeting DTSL can function as a new strategy for cancer treatment.

A hydrodynamic-based microfluidic chip consisted of two function units that could not only separate tumor cells (TCs) from whole blood but also remove residual blood cells was designed. The separation of TCs was achieved by a straight contraction-expansion array (CEA) microchannel on the front end of the chip. The addition of contractive structure brought a micro-vortex like Dean vortex that promoted cell focusing in the channel, while when cells entered the dilated region, the wall-induced lift force generated by the channel wall gave cells a push away from the wall. As the wall-induced lift force is proportional to the third power of the cell diameter, TCs with larger diameter will have a larger lateral migration under the wall-induced lift force, realizing the separation of TCs from blood sample. Fluorescent particles with diameters of 19.3 μm and 4.5 μm were used to simulate TCs and red blood cells, respectively, to verify the separation capacity of the proposed CEA microchannel for particles with different diameter. And a separation efficiency 98.7% for 19.3 μm particles and a removal rate 96.2% for 4.5 μm particles was observed at sample flow rate of 10 μL min-1 and sheath flow rate of 190 μL min-1. In addition, a separation efficiency about 96.1% for MCF-7 cells (stained with DiI) and removal rates of 96.2% for red blood cells (RBCs) and 98.7% for white blood cells (WBCs) were also obtained under the same condition. However, on account of the large number of blood cells in the blood, there will be a large number of blood cells remained in the isolated TCs, so a purification unit based on hydrodynamic filtration (HDF) was added after the separation microchannel. The purification channel is a size-dictated cell filter that can remove residual blood cells but retain TCs, thus achieving the purification of TCs. Combined the CEA microchannel and the purifier, the microchip facilitates sorting of MCF-7 cells from whole blood with a separation rate about 95.3% and a removal rate over 99.99% for blood cells at a sample flow rate of 10 μL min-1, sheath flow rate of 190 μL min-1 and washing flow rate of 63 μL min-1.