The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their ...capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.
As a thriving member of the 2D nanomaterials family, MXenes, i.e., transition metal carbides, nitrides, and carbonitrides, exhibit outstanding electrochemical, electronic, optical, and mechanical ...properties. They have been exploited in many applications including energy storage, electronics, optoelectronics, biomedicine, sensors, and catalysis. Compared to other 2D materials, MXenes possess a unique set of properties such as high metallic conductivity, excellent dispersion quality, negative surface charge, and hydrophilicity, making them particularly suitable as inks for printing applications. Printing and pre/post‐patterned coating methods represent a whole range of simple, economically efficient, versatile, and eco‐friendly manufacturing techniques for devices based on MXenes. Moreover, printing can allow for complex 3D architectures and multifunctionality that are highly required in various applications. By means of printing and patterned coating, the performance and application range of MXenes can be dramatically increased through careful patterning in three dimensions; thus, printing/coating is not only a device fabrication tool but also an enabling tool for new applications as well as for industrialization.
Recent progress in the deposition/patterning of MXenes through printing and coating methods is summarized, including issues that are related to the formulation of MXene inks (e.g., dispersion, stability, and tuning of physical–chemical and morphological properties), relevant printing/coating methods, and their applications in energy storage, electronics/optoelectronics, sensing, and actuation.
Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long ...been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.
Background
Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for ...guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs.
Materials and Methods
By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts (n = 183 and 214).
Results
We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive +), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative −, CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway.
Conclusion
We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.
Implications for Practice
An immunohistochemistry (IHC)‐based classification approach was developed for triple‐negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression‐based classification. This IHC‐based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype‐specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice.
Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar ...metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.
Hydrogels have recently garnered tremendous interest due to their potential application in soft electronics, human-machine interfaces, sensors, actuators, and flexible energy storage. Benefiting from ...their impressive combination of hydrophilicity, metallic conductivity, high aspect ratio morphology, and widely tuneable properties, when two-dimensional (2D) transition metal carbides/nitrides (MXenes) are incorporated into hydrogel systems, they offer exciting and versatile platforms for the design of MXene-based soft materials with tunable application-specific properties. The intriguing and, in some cases, unique properties of MXene hydrogels are governed by complex gel structures and gelation mechanisms, which require in-depth investigation and engineering at the nanoscale. On the other hand, the formulation of MXenes into hydrogels can significantly increase the stability of MXenes, which is often the limiting factor for many MXene-based applications. Moreover, through simple treatments, derivatives of MXene hydrogels, such as aerogels, can be obtained, further expanding their versatility. This tutorial review intends to show the enormous potential of MXene hydrogels in expanding the application range of both hydrogels and MXenes, as well as increasing the performance of MXene-based devices. We elucidate the existing structures of various MXene-containing hydrogel systems along with their gelation mechanisms and the interconnecting driving forces. We then discuss their distinctive properties stemming from the integration of MXenes into hydrogels, which have revealed an enhanced performance, compared to either MXenes or hydrogels alone, in many applications (energy storage/harvesting, biomedicine, catalysis, electromagnetic interference shielding, and sensing).
When two-dimensional transition metal carbides/nitrides (MXenes) meet hydrogels, they offer versatile platforms for designing novel soft materials with exciting properties.
Rational design of non‐noble metal catalysts with robust and durable electrocatalytic activity for oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction ...(HER) is extremely important for renewable energy conversion and storage, regenerative fuel cells, rechargeable metal–air batteries, water splitting etc. In this work, a unique hybrid material consisting of Fe3C and Co nanoparticles encapsulated in a nanoporous hierarchical structure of N‐doped carbon (Fe3C‐Co/NC) is fabricated for the first time via a facile template‐removal method. Such an ingenious structure shows great features: the marriage of 1D carbon nanotubes and 2D carbon nanosheets, abundant active sites resulting from various active species of Fe3C, Co, and NC, mesoporous carbon structure, and intimate integration among Fe3C, Co, and NC. As a multifunctional electrocatalyst, the Fe3C‐Co/NC hybrid exhibits excellent performance for ORR, OER, and HER, outperforming most of reported triple functional electrocatalysts. This study provides a new perspective to construct multifunctional catalysts with well‐designed structure and superior performance for clean energy conversion technologies.
A hybrid material of Fe3C‐Co/NC is synthesized through a facile template‐removal method, where Fe3C and Co nanoparticles are encapsulated in a nanoporous N‐doped hierarchical structure integrating 1D carbon nanotubes and 2D carbon nanosheets. As a multifunctional electrocatalyst, such a hybrid exhibits superior catalytic performances for oxygen reduction reaction, oxygen evolution reaction and hydrogen evolution reaction simultaneously.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC ...intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.
Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of ...nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.
Formic acid (HCOOH) is one of the most promising chemical fuels that can be produced through CO2 electroreduction. However, most of the catalysts for CO2 electroreduction to HCOOH in aqueous solution ...often suffer from low current density and limited production rate. Herein, we provide a bismuth/cerium oxide (Bi/CeOx) catalyst, which exhibits not only high current density (149 mA cm−2), but also unprecedented production rate (2600 μmol h−1 cm−2) with high Faradaic efficiency (FE, 92 %) for HCOOH generation in aqueous media. Furthermore, Bi/CeOx also shows favorable stability over 34 h. We hope this work could offer an attractive and promising strategy to develop efficient catalysts for CO2 electroreduction with superior activity and desirable stability.
The limited current density, production rate as well as selectivity hinder the improvement of HCOOH production from CO2 electroreduction. Here, bismuth/cerium oxide (Bi/CeOx) displays outstanding performances for CO2 electroreduction to HCOOH, which not only shows excellent selectivity, but also achieves a high current density (149 mA cm−2) and especially the maximum HCOOH production rate (2600 μmol h−1 cm−2) ever reported.
PDF
