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.
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.
Background and Aims
There is growing evidence that single‐stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less ...clear, however, what role circRNA plays in HCC metastasis.
Approach and Results
In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs. In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, and in vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), both of which are tumor suppressors in HCC. We found that mitogen‐activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)‐1 were direct common targets for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR‐326/miR‐532‐5p‐MAPK1 signaling and, furthermore, mediates tumor‐associated macrophage infiltration by regulating the miR‐326/miR‐532‐5p‐CSF‐1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF‐1, MAPK1, and CD68+ tumor‐associated macrophages, all of which were predictive of patient outcomes.
Conclusion
We identified circASAP1 as a key regulator of HCC metastasis that acts on miR‐326/miR‐532‐5p‐MAPK1/CSF‐1 signaling and serves as a prognostic predictor in patients with HCC.
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.
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor ...(LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer.
FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18–70 years, with an Eastern Cooperative Oncology Group performance status of 0–1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989).
Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2–29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months 95% CI 8·6–15·2) than in the control group (5·8 months 4·0–6·7; hazard ratio 0·44 95% CI 0·30–0·65; p<0·0001). The most common grade 3–4 treatment-related adverse events were neutropenia (21 30% of 69 in the pooled subtyping-based group vs 16 23% of 70 in the control group), anaemia (five 7% vs none), and increased alanine aminotransferase (four 6% vs one 1%). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group.
These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway.
National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals.
For the Chinese translation of the abstract see Supplementary Materials section.
Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale ...metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear WVI secondary building units and photosensitizing 5,10,15,20‐tetra(p‐benzoato)porphyrin (TBP) ligands, cationic W‐TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.
A metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). The enhanced antigen presentation synergizes with checkpoint blockade immunotherapy to expand and reinvigorate cytotoxic T cells, leading to 97 % tumor regression in a bilateral breast cancer model.
Sodium-ion batteries (SIBs) have shown promising prospects for complementarity to lithium-ion batteries (LIBs) in the field of grid-scale energy storage. After a decade of continuous fundamental ...research on SIBs, it's becoming increasingly urgent to advance the commercialization. For SIB anode materials, hard carbon is the most mature and currently the only material likely to be commercialized, but it is still far away from large-scale industrialization. Herein, we carry out a comprehensive overview of the current state of the art in terms of three main aspects. Firstly, a fundamental understanding of the microstructure and sodium storage mechanism of hard carbon is introduced, which can be categorized into three different processes: capacitive adsorption, nanopore filling, and intercalation in carbon interlayers. Then, based on an in-depth understanding of the sodium storage mechanism, optimization methods in terms of increasing the specific capacity, rate performance, initial coulombic efficiency (ICE), and long-cycling stability are comprehensively summarized and analyzed. Finally, potential methods and associated benefits for the design of carbon structures and the solid electrolyte interface (SEI) are discussed, hoping to provide useful guidelines for future research and commercialization.
The sodium storage mechanism of hard carbon, optimization strategies of electrochemical performance, and the scientific challenges towards the commercialization of sodium-ion batteries were systematically summarized and analyzed.
Nickel‐rich layered transition metal oxides are considered as promising cathode candidates to construct next‐generation lithium‐ion batteries to satisfy the demands of electrical vehicles, because of ...the high energy density, low cost, and environment friendliness. However, some problems related to rate capability, structure stability, and safety still hamper their commercial application. In this Review, beginning with the relationships between the physicochemical properties and electrochemical performance, the underlying mechanisms of the capacity/voltage fade and the unstable structure of Ni‐rich cathodes are deeply analyzed. Furthermore, the recent research progress of Ni‐rich oxide cathode materials through element doping, surface modification, and structure tuning are summarized. Finally, this review concludes by discussing new insights to expand the field of Ni‐rich oxides and promote practical applications.
Nickel for better batteries: This Review systematically summarizes Ni‐rich layered materials as cathodes for lithium‐ion batteries through six aspects: synthesis, mechanism, element doping, surface coating, compositional partitioning, and electrolyte adjustment with the aim to boost the development and achieve expectations.
Silicon monoxide (SiO) has been explored and confirmed as a promising anode material of lithium‐ion batteries. Compared with pure silicon, SiO possesses a more stable microstructure which makes ...better comprehensive electrochemical properties. However, the lithiation mechanism remains in dispute, and problems such as poor cyclability, unsatisfactory electrical conductivity, and low initial Coulombic efficiency (ICE) need to be addressed. Additionally, more attention needs to be paid on the internal relationship between electrochemical performances and structures. In this review, the different preparation processes, the derived microstructure of the SiOx, the corresponding lithiation mechanism, and electrochemical properties are summarized. Researches about disproportionation reaction which is regarded as a key point and other modifications are systematically introduced. Closely linked with structure, the advantages and disadvantages of various SiOx anode materials are summarized and analyzed, and the possible directions toward the practical applications of SiOx anode material are presented. In a word, from the preparation and reaction mechanism of the material to the modifications and future development, a complete and systematical review on SiOx anode is presented.
Silicon monoxide (SiO) is researched and applied as a promising anode material for lithium‐ion batteries (LIBs). It is started from the preparation and microstructure of SiO, and modification is introduced including disproportionation, constructing composites, design of microstructure, different binders, and prelithiation. Also, the advantages and disadvantages are discussed from the perspective of practical application.
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