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Background: The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan-cancers., Methods: Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross-validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model., Results: A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36-62.65 months). In the training cohort of 1425 patients, through Lasso regression cross-validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C-indexes of the model for predicting 1-, 3-, 5-, and 10-year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723-8.397; log-rank p < 0.001; validation cohort: HR, 8.429; 95% CI, 6.180-11.497; log-rank p < 0.001)., Conclusion: The prognostic model based on the nutritional indexes of pan-cancer can divide patients into different survival risk groups and performed well in the validation cohort., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

The complexity and heterogeneity of individual tumors have hindered the efficacy of existing therapeutic cancer vaccines, sparking intensive interest in the development of more effective in situ vaccines. Herein, we introduce a cancer nanovaccine for reactive oxygen species-augmented metalloimmunotherapy in which FeAl-layered double hydroxide (LDH) is used as a delivery vehicle with dihydroartemisinin (DHA) as cargo. The LDH framework is acid-labile and can be degraded in the tumor microenvironment, releasing iron ions, aluminum ions, and DHA. The iron ions contribute to aggravated intratumoral oxidative stress injury by the synergistic Fenton reaction and DHA activation, causing apoptosis, ferroptosis, and immunogenic cell death in cancer cells. The subsequently released tumor-associated antigens with the aluminum adjuvant form a cancer nanovaccine to generate robust and long-term immune responses against cancer recurrence and metastasis. Moreover, Fe ion-enabled T 1 -weighted magnetic resonance imaging can facilitate real-time tumor therapy monitoring. This cancer-nanovaccine-mediated metalloimmunotherapy strategy has the potential for revolutionizing the precision immunotherapy landscape.

Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rβγ was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (-/-) and CD11c+ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings., (©2023 American Association for Cancer Research.)

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Tumor microenvironment (TME) stimuli-responsive nanoassemblies are emerging as promising drug delivery systems (DDSs), which acquire controlled release by structural transformation under exogenous stimulation. However, the design of smart stimuli-responsive nanoplatforms integrated with nanomaterials to achieve complete tumor ablation remains challenging. Therefore, it is of utmost importance to develop TME-based stimuli-responsive DDSs to enhance drug-targeted delivery and release at tumor sites. Herein, we proposed an appealing strategy to construct fluorescence-mediated TME stimulus-responsive nanoplatforms for synergistic cancer therapy by assembling photosensitizers (PSs) carbon dots (CDs), chemotherapeutic agent ursolic acid (UA), and copper ions (Cu 2+ ). First, UA nanoparticles (UA NPs) were prepared by self-assembly of UA, then UA NPs were assembled with CDs via hydrogen bonding force to obtain UC NPs. After combining with Cu 2+ , the resulting particles (named UCCu 2+ NPs) exhibited quenched fluorescence and photosensitization due to the aggregation of UC NPs. Upon entering the tumor tissue, the photodynamic therapy (PDT) and the fluorescence function of UCCu 2+ were recovered in response to TME stimulation. The introduction of Cu 2+ triggered the charge reversal of UCCu 2+ NPs, thereby promoting lysosomal escape. Furthermore, Cu 2+ resulted in additional chemodynamic therapy (CDT) capacity by reacting with hydrogen peroxide (H 2 O 2 ) as well as by consuming glutathione (GSH) in cancer cells through a redox reaction, hence magnifying intracellular oxidative stress and enhancing the therapeutic efficacy due to reactive oxygen species (ROS) therapy. In summary, UCCu 2+ NPs provided an unprecedented novel approach for improving the therapeutic efficacy through the three-pronged (chemotherapy, phototherapy, and heat-reinforced CDT) attacks to achieve synergistic therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The tumor microenvironment (TME) is crucial in cancer progression, and the extracellular matrix (ECM) is an important TME component. Collagen is a major ECM component that contributes to tumor cell infiltration, expansion, and distant metastasis during cancer progression. Recent studies reported that collagen is deposited in the TME to form a collagen wall along which tumor cells can infiltrate and prevent drugs from working on the tumor cells. Collagen-tumor cell interaction is complex and requires the activation of multiple signaling pathways for biochemical and mechanical signaling interventions. In this review, we examine the effect of collagen deposition in the TME on tumor progression and discuss the interaction between collagen and tumor cells. This review aims to illustrate the functions and mechanisms of collagen in tumor progression in the TME and its role in tumor therapy. The findings indicated collagen in the TME appears to be a better target for cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

By combining mass-spectrometry-based proteomics and phosphoproteomics with genomics, epi-genomics, and transcriptomics, proteogenomics provides comprehensive molecular characterization of cancer. Using this approach, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has characterized over 1,000 primary tumors spanning 10 cancer types, many with matched normal tissues. Here, we present LinkedOmicsKB, a proteogenomics data-driven knowledge base that makes consistently processed and systematically precomputed CPTAC pan-cancer proteogenomics data available to the public through ∼40,000 gene-, protein-, mutation-, and phenotype-centric web pages. Visualization techniques facilitate efficient exploration and reasoning of complex, interconnected data. Using three case studies, we illustrate the practical utility of LinkedOmicsKB in providing new insights into genes, phosphorylation sites, somatic mutations, and cancer phenotypes. With precomputed results of 19,701 coding genes, 125,969 phosphosites, and 256 genotypes and phenotypes, LinkedOmicsKB provides a comprehensive resource to accelerate proteogenomics data-driven discoveries to improve our understanding and treatment of human cancer. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests B.Z. received consulting fees from AstraZeneca., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data., Competing Interests: Declaration of interests F.A. is an inventor on a patent application related to SignatureAnalyzer-GPU filed by the Broad Institute and is an employee and shareholder of Illumina Inc. since 8 November 2021., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer., Competing Interests: Declaration of interests No interests are declared by the author., (Copyright © 2023 Elsevier Inc. All rights reserved.)

CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less intertumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing.

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells. The self-ligand receptor of the signalling lymphocytic activation molecule family member 7 (SLAMF7), a molecule that is critical in promoting the body's innate immune cells to detect and engulf cancer cells, is expressed nearly exclusively on the cell surface of haematologic tumours, but not on solid ones. Here we show that a bispecific nanobioconjugate that enables the decoration of SLAMF7 on the surface of solid tumours induces robust phagocytosis and activates the phagocyte cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, sensitizing the tumours to immune checkpoint blockade. Our findings support an immunological conversion strategy that uses nano-adjuvants to improve the effectiveness of immunotherapies for solid tumours., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Adenosine triphosphate (ATP) is an important biomolecule, which is the primary source of cellular energy. In particular, an abnormal metabolism of ATP level has been took part in many diseases, such as cancer. Thus, developing an effective fluorescent probe for tumor-targeting imaging of ATP is great importance for in-depth understanding the functions of ATP in tumor invasion and matastasis. In this work, we present the design and synthesis of a tumor-targeting near-infrared (NIR) fluorescent probe named Bio-SiR. Bio-SiR is mainly composed of three parts: si-rhodamine-based fluorophore, diethylenetriamine-based recognition group and biotin-based tumor-targetable group. When Bio-SiR reacts with ATP, a turn-on fluorescence at 675 nm (NIR region) is observed clearly, which is suitable for its application in mice. In addition, due to a concurrent effect from dual recognition sites, the probe Bio-SiR displays excellent selectivity for ATP over other potential biological analytes. Under the guidance of biotin group, Bio-SiR can be successfully used for imaging ATP in cancer cells. Furthermore, live-cell imaging allows us to directly real-time monitor the dynamic change of ATP in cancer cells. In particular, this is the first tumor-targeting NIR small-molecule fluorescent probe for endogenous ATP imaging in tumor-bearing mice. These features demonstrate that this probe is a useful imaging tool for expounding the function of ATP in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Therapeutics that can be activated by radiation in situ to enhance the efficacy of radiotherapy are highly desirable. Herein, 7-Dehydrocholesterol (7-DHC), a biosynthetic precursor of cholesterol, as a radiosensitizer, exploiting its ability to propagate the free radical chain reaction is explored. The studies show that 7-DHC can react with radiation-induced reactive oxygen species and in turn promote lipid peroxidation, double-strand breaks, and mitochondrial damage in cancer cells. For efficient delivery, 7-DHC is encapsulated into poly(lactic-co-glycolic acid) nanoparticles, forming 7-DHC@PLGA NPs. When tested in CT26 tumor bearing mice, 7-DHC@PLGA NPs significantly enhanced the efficacy of radiotherapy, causing complete tumor eradication in 30% of the treated animals. After treatment, 7-DHC is converted to cholesterol, causing no detectable side effects or hypercalcemia. 7-DHC@PLGA NPs represent a radiation-responsive sensitizer with great potential in clinical translation., (© 2022 Wiley-VCH GmbH.)

CEMIP was initially identified as an inner-ear specific protein in which three-point mutations cause folding changes in protein structure associated with non-syndromic hearing loss. CEMIP was also involved in other cellular activities, such as hyaluronan depolymerization independent of CD44 and other hyaluronidases. Growing evidence has demonstrated that CEMIP is involved in the progression of various tumors. However, whether the oncogenic effects of CEMIP relies on its enzymatic activity remain elusive. CEMIP is significantly related to metastasis and poor prognosis in patients with various tumors, suggesting that CEMIP is a potential, highly specific diagnostic tumor marker. Most preclinical experiments have shown that the overexpression of CEMIP in tumors mainly affects the adhesion, metastasis, and invasion of tumor cells and EMT. Other studies have also demonstrated that CEMIP can promote a variety of tumor processes by affecting tumor proliferation, dedifferentiation, and the tumor microenvironment. In terms of molecular mechanisms, existing research has shown that CEMIP mainly affects the WNT and EGFR signaling pathways. In addition, a variety of miRNAs have been shown to inhibit CEMIP in tumors. This paper elaborates on the clinical characteristics and regulatory dysfunction of CEMIP in different cancers. CEMIP provides a new potential target for therapy of multiple tumors, which is worthy of further study., (Copyright © 2021. Published by Elsevier Masson SAS.)

A novel theranostic probe called CX-B-DF is constructed for precise chemotherapy guided by near-infrared (NIR) fluorescence imaging. Moreover, the theranostic probe shows high cytotoxicity to cancer cells under dual activation (H 2 O 2 and TP), which causes the accuracy of drug release to be improved and the toxic side effects to be reduced.

Dendritic cells (DCs) play a pivotal role in initiating antigen-specific tumor immunity. However, the abnormal function of DCs owing to the immunosuppressive tumor microenvironment (TME) and the insufficient number of tumor infiltrating DCs could promote immune tolerance and tumor immune escape. Thus, there is great potential to employ DCs to induce efficient antitumor immunity. In this paper, we developed intelligent DCs (iDCs), which consist of nanoparticles loaded with photothermal agents (IR-797) and coated with a mature DC membrane. The DC cell membrane on the surface of iDCs preserves the ability to present antigens and prime T cells. The iDCs can also enter the lymph node and stimulate T cells. The activated T cells reduced the expression of heat shock proteins (HSPs) in tumor cells, rendering them more sensitive to heat stress. Subsequently, we used mild photothermal therapy (42-45 °C) to induce immunogenic cell death and contribute to a synergistic antitumor effect. iDCs as a refined and precise system in combination with DC-based immunotherapy and thermal therapy can be stored long-term and on a large scale, so they can be applied in many patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Iodine has shown promise in enhancing radiotherapy. However, conventional iodine compounds show fast clearance and low retention inside cancer cells, limiting their application as a radiosensitizer. Herein, we synthesize poly(maleic anhydride- alt -1-octadecene) coated KI nanoparticles (PMAO-KI NPs) and evaluate their potential for enhancing radiotherapy. Owing to the polymer coating, the KI core of PMAO-KI NPs is not instantly dissolved in aqueous solutions but slowly degraded, allowing for controlled release of iodide (I - ). I - is transported into cells via the sodium iodide symporter (NIS), which is upregulated in breast cancer cells. Our results show that PMAO-KI NPs can enhance radiation-induced production of reactive oxygen species such as hydroxyl radicals. When tested in vitro with MCF-7 cells, PMAO-KI NPs promote radiation-induced DNA double-strand breaks and lipid peroxidation, causing a drop in cancer cell viability and reproductivity. When tested in MCF-7 bearing mice, PMAO-KI NPs show significant radiosensitizing effects, leading to complete tumor eradication in 80% of the treated animals without inducing additional toxicity. Overall, our strategy exploits electrolyte nanoparticles to deliver iodide into cancer cells through NIS, thus promoting radiotherapy against breast cancer.

Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.

Cancer ranks as a leading cause of death in every country of the world. However, if they are discovered early, a lot of cancers can be prevented or cured. Discovering and monitoring cancer markers are the main methods for early diagnosis of cancer. To date, many fluorescent probes designed and used for early cancer diagnosis can only react with a single marker, which always causes insufficient accuracy in complex systems. Herein, a novel near-infrared (NIR) fluorescent probe (CyO-DNP) for the sequential detection of H 2 S and H + is synthesized. In this probe, a heptamethine dye is selected as the fluorophore and a 2,4-dinitrophenyl (DNP) ether is chosen as recognition group. In the presence of H 2 S, CyO-DNP is transformed into CyO, which exhibits an intense fluorescence at 663 nm. Then, H + induces the protonation of CyO to obtain CyOH, and the final fluorescence emission at 793 nm significantly enhances. Owing to the low cytotoxicity and the NIR fluorescence emission, CyO-DNP can sequentially monitor endogenous H 2 S and H + in cancer cells and image exogenous and endogenous H 2 S and H + in mice. It is worth mentioning that CyO-DNP can effectively avoid the false positive signal caused by the liver and kidney and discriminate normal mice and tumor mice accurately. For all we know, CyO-DNP is the first fluorescent probe for early accurate diagnosis of cancer by sequentially detecting H 2 S and H + .

As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins., (© 2021. The Author(s).)

Epithelial Protein Lost In Neoplasm (EPLIN), also known as LIMA1 (LIM Domain And Actin Binding 1), was first discovered as a protein differentially expressed in normal and cancerous cell lines. It is now known to be key to the progression and metastasis of certain solid tumours. Despite a slow pace in understanding the biological role in cells and body systems, as well as its clinical implications in the early years since its discovery, recent years have witnessed a rapid progress in understanding the mechanisms of this protein in cells, diseases and indeed the body. EPLIN has drawn more attention over the past few years with its roles expanding from cell migration and cytoskeletal dynamics, to cell cycle, gene regulation, angiogenesis/lymphangiogenesis and lipid metabolism. This concise review summarises and discusses the recent progress in understanding EPLIN in biological processes and its implications in cancer.

The discovery of immune checkpoint blockade has revolutionized the field of immuno-oncology and established the foundation for developing various new therapies that can surpass conventional cancer treatments. Most recent immunotherapeutic strategies have focused on adaptive immune responses by targeting T cell-activating pathways, genetic engineering of T cells with chimeric antigen receptors, or bispecific antibodies. Despite the unprecedented clinical success, these T cell-based treatments have only benefited a small proportion of patients. Thus, the need for the next generation of cancer immunotherapy is driven by identifying novel therapeutic molecules or new immunoengineered cells. To maximize the therapeutic potency via innate immunogenicity, the convergence of innate immunity-based therapy and biomaterials is required to yield an efficient index in clinical trials. This review highlights how biomaterials can efficiently reprogram and recruit innate immune cells in tumors and ultimately initiate activation of T cell immunity against advanced cancers. Moreover, the design and specific biomaterials that improve innate immune cells' targeting ability to selectively activate immunogenicity with minimal adverse effects are discussed., (© 2021 Wiley-VCH GmbH.)

The immunosuppressive and hypoxic tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we showed that elevated levels of Delta-like 1 (DLL1) in the breast and lung TME induced long-term tumor vascular normalization to alleviate tumor hypoxia and promoted the accumulation of interferon γ (IFN-γ)-expressing CD8 + T cells and the polarization of M1-like macrophages. Moreover, increased DLL1 levels in the TME sensitized anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) treatment in its resistant tumors, resulting in tumor regression and prolonged survival. Mechanically, in vivo depletion of CD8 + T cells or host IFN-γ deficiency reversed tumor growth inhibition and abrogated DLL1-induced tumor vascular normalization without affecting DLL1-mediated macrophage polarization. Together, these results demonstrate that elevated DLL1 levels in the TME promote durable tumor vascular normalization in a CD8 + T cell- and IFN-γ-dependent manner and potentiate anti-CTLA4 therapy. Our findings unveil DLL1 as a potential target to persistently normalize the TME to facilitate cancer immunotherapy., Competing Interests: The authors declare no competing interest.

A near-infrared fluorescent probe, CyAc, is synthesized for accurately diagnosing cancer in vivo by sequential detection of Cys and H + . CyAc can not only achieve a good distinction between normal cells and cancer cells, but also distinguish normal mice from tumor mice.

Nuclear protein‑1 (NUPR1) is also known as Com‑1 or p8. It is a protein primarily found in the nucleus of various cells, including cancer cells, and it has been found to play an important role in cell stress and stress‑related apoptosis. Over the past two decades, NUPR1 has been firmly indicated to play a role in the development and progression of numerous types of cancer, as well as in a number of other pathological conditions, including pancreatitis, diabetes, neurological and inflammatory conditions. The past decade has witnessed a rapid understanding of the biological and cellular mechanisms through which NUPR1 operates on cells and the identification of new variant of the protein. Most importantly, there have been comprehensive studies on the clinical and pathological aspects of NUPR1 and its variant in multiple malignancies and identification of therapeutic methods by targeting the protein. The present review aimed to summarise the current knowledge relating to NUPR1 in human malignancies and to discuss the associated controversies and potential future prospects of this molecule.

The reduced coenzymes (NADH and NADPH) are an important product in energy metabolism and closely related to the occurrence and development of cancer. So it is necessary to use a powerful detection tool to visualize NAD(P)H in energy metabolism of tumor cells and find a new strategy to improve cancer treatment based on NAD(P)H. Herein, a novel multifunctional probe (Cy-N) is synthesized with good near-infrared fluorescence (NIRF) response to NAD(P)H and the photoacoustic (PA) and photothermal properties are successfully activated by NAD(P)H. The probe is successfully applied in visualizing NAD(P)H in energy metabolism of tumor cells and imaging NAD(P)H in bacteria. Moreover, the probe can be used to image NAD(P)H in energy metabolism of tumor-bearing mice by dual-modal imaging (NIRF and PA). More importantly, in terms of the role of NAD(P)H in energy metabolism, the photothermal therapy (PTT) is activated by NAD(P)H and a novel strategy of enhanced PTT is proposed by injecting glucose. As far as we know, this is the first probe to detect NAD(P)H in energy metabolism through dual-modal imaging, and also the first probe to activate PTT based on NAD(P)H, which will provide important information of the diagnosis and treatment of cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite improvements in therapy and management, cancer represents and remains a major cause of mortality and morbidity worldwide. Although genetics serve an important role in tumorigenesis and tumour progression, the tumour microenvironment (TME) in solid tumours is also important and has been indicated to contribute to these processes. Stromal cell‑derived factors (SDFs) represent an important family within the TME. The family includes SDF‑1, SDF‑2, SDF2‑like 1 (SDF2L1), SDF‑3, SDF‑4 and SDF‑5. SDF‑1 has been demonstrated to act as a positive regulator in a number of types of tumour, such as oesophago‑gastric, pancreatic, lung, breast, colorectal and ovarian cancer, while the biology and functions of other members of the SDF family, including SDF‑2, SDF2L1, SDF‑4 and SDF‑5, in cancer are different, complex and controversial, and remain mainly unknown. Full identification and understanding of the SDFs across multiple types of cancer is required to elucidate their function and establish potential key targets in cancer.

Immunotherapy is known to be clinically beneficial for cancer patients and in many cases represents the new standard of care. Because of this success, the interest in integrating nanomedicine with cancer immunotherapy to further improve clinical response and toxicity profiles has grown. However, unlike conventional systemic therapies, which are directly cytotoxic to tumour cells, cancer immunotherapy relies on the host's immune system to generate tumouricidal effects. As such, proper design of cancer immune nanomedicine requires scrutiny of tumours' intrinsic and extrinsic factors that may impact host antitumour immunity. Here, we highlight key parameters that differentiate cancer immunotherapy from conventional cytotoxic agents, and we discuss their implications for designing preclinical cancer immune nanomedicine studies. We emphasize that these factors, including intratumoural genomic heterogeneity, commensal diversity, sexual dimorphism and biological ageing, which were largely ignored in traditional cancer nanomedicine experiments, should be carefully considered and incorporated into cancer immune nanomedicine investigations given their critical involvement in shaping the body's antitumour immune responses.

Background: A growing number of studies have suggested that the Long intergenic noncoding RNA 00511 (LINC00511) is aberrantly expressed in multiple malignancies and is related to patient survival. Herein, we conducted a systematic review and meta-analysis to comprehensively evaluate the prognostic significance of LINC00511 in human malignancies., Methods: Eligible studies published by March 11, 2020 were identified in 4 electronic databases including PubMed, EMBASE, Web of Science, and the Chinese National Knowledge Infrastructure. Hazard ratios and 95% confidence intervals (CIs) were used to evaluate the prognostic significance of LINC00511 expression in malignant tumors. The association between LINC00511 expression and cancer clinicopathologic features were assessed using Odds ratios (ORs) and CIs., Results: A total of 13 studies, comprising 1,053 patients, were included in the meta-analysis. The calculated hazard ratio was 2.00 (95% CI: 1.59-2.52, P < .000), suggesting that higher LINC00511 expression could predict poorer overall survival in patients with malignancies. Additionally, our statistical analysis indicated that elevated LINC00511 expression closely associated with bigger tumors (OR = 2.92, 95% CI 1.65-5.18, P < .000), higher incidence of lymph node metastasis (OR = 3.46, 95% CI 2.11-5.66, P < .000) and distant metastasis (OR = 2.40, 95% CI 1.14-5.05, P = .02), poorer differentiation (OR = 1.55, 95% CI 1.11-2.16, P = .01), as well as more advanced TNM stage (OR = 3.90, 95% CI 2.70-5.63, P < .000)., Conclusions: High LINC00511 expression may predict unfavorable prognosis in patients with malignancies. It should be further explored as a potential prognostic and therapeutic biomarker for human cancer.

The unprecedented benefits of immunotherapy in advanced malignancies have resulted in increased interests in exploiting immune stimulatory agents in earlier-stage solid tumors in the neoadjuvant setting. However, systemic delivery of immunotherapies may cause severe immune-related side-effects and hamper the development of combination treatments. Intratumoral delivery of neoadjuvant immunotherapy provides a promising strategy in harnessing the power of immunotherapy while minimizing off-target toxicities. The direct injection of immune stimulating agents into the tumor primes the local tumor-specific immunity to generate a systemic, durable clinical response. Intratumoral immunotherapy is a highly active area of investigation resulting in a plethora of agents, for example, immune receptor agonists, non-oncolytic and oncolytic viral therapies, being tested in preclinical and clinical settings. Currently, more than 20 neoadjuvant clinical trials exploring distinct intratumoral immune stimulatory agents and their combinations are ongoing. Practical considerations, including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here, we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care., (©2020 American Association for Cancer Research.)

Immune checkpoint blockade (ICB) has shown long-term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment-induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti-CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti-CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti-CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy., (© 2019 UICC.)

Many inorganic nanoparticles are prepared and their behaviors in living systems are investigated. Yet, common electrolytes such as NaCl are left out of this campaign. The underlying assumption is that electrolyte nanoparticles will quickly dissolve in water and behave similarly as their constituent salts. Herein, this preconception is challenged. The study shows that NaCl nanoparticles (SCNPs) but not salts are highly toxic to cancer cells. This is because SCNPs enter cells through endocytosis, bypassing cell regulations on ion transport. When dissolved inside cancer cells, SCNPs cause a surge of osmolarity and rapid cell lysis. Interestingly, normal cells are much more resistant to the treatment due to their relatively low sodium levels. Unlike conventional chemotherapeutics, SCNPs cause immunogenic cell death or ICD. In vivo studies show that SCNPs not only kill cancer cells, but also boost an anticancer immunity. The discovery opens up a new perspective on nanoparticle-based therapeutics., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47-signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.

The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.

Immune cells rely on a functional vascular network to enter tissues. In solid tumors, blood vessels are abnormal and dysfunctional and, thus, immune effector cell infiltration is impaired. Although normalizing the tumor vasculature has been shown to improve the efficacy of cancer immunotherapies, recent studies suggest that enhanced immune stimulation also, in turn, improves tumor vascular normalization. Thus, this new paradigm of immune system-tumor vasculature mutual reprogramming opens the possibility of identifying new cancer treatment strategies that combine vascular targeting and immunotherapies. Here, we highlight current evidence supporting immune system-tumor vasculature crosstalk and outline how this relationship can provide new rationales for developing more effective combination immunotherapy strategies for treating human cancers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design., (©2018 American Association for Cancer Research.)

Nanomaterials offer unique advantages as drug-delivery vehicles for cancer therapeutics. For immuno-oncology applications, cancer nanomedicine should be developed beyond drug-delivery platforms. A greater emphasis on actively modulating host anticancer immunity using nanomaterials provides new avenues for developing novel cancer therapeutics.

The vasculature of tumours is highly abnormal and dysfunctional. Consequently, immune effector cells have an impaired ability to penetrate solid tumours and often exhibit compromised functions. Normalization of the tumour vasculature can enhance tissue perfusion and improve immune effector cell infiltration, leading to immunotherapy potentiation. However, recent studies have demonstrated that the stimulation of immune cell functions can also help to normalize tumour vessels. In this Opinion article, we propose that the reciprocal regulation between tumour vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumour immune microenvironment to induce durable antitumour immunity. A deeper understanding of these pathways could pave the way for identifying new biomarkers and developing more effective combination treatment strategies for patients with cancer.

The mechanistic complexes of kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) bind and integrate a variety of cellular cues to mediate neuronal activities such as neuronal differentiation, survival, and cytoskeleton remodelling by interacting with a variety of binding partners. Accumulated evidence has also indicated its role in the regulation of vascular development. Mice with Kidins220 knockdown phenotypically present with cardiovascular abnormalities. Kidins220 also contributes to immunomodulation in combination with B cells and T cells. Moreover, emerging evidence has revealed that this protein regulates many crucial cellular processes and thus has been implicated in an increasing number of malignancies. Here, we review recent advances in our understanding of Kidins220 and its role in cancer development. Further investigation is warranted to shed light on the role played by Kidins220 in the dynamic arrangement of the cytoskeleton and epithelial-mesenchymal transition, and its implication in tumourigenesis and cancer progression.

Tumour-targeted immunotherapy offers the unique advantage of specific tumouricidal effects with reduced immune-associated toxicity. However, existing platforms suffer from low potency, inability to generate long-term immune memory and decreased activities against tumour-cell subpopulations with low targeting receptor levels. Here we adopted a modular design approach that uses colloidal nanoparticles as substrates to create a multivalent bi-specific nanobioconjugate engager (mBiNE) to promote selective, immune-mediated eradication of cancer cells. By simultaneously targeting the human epidermal growth factor receptor 2 (HER2) expressed by cancer cells and pro-phagocytosis signalling mediated by calreticulin, the mBiNE stimulated HER2-targeted phagocytosis and produced durable antitumour immune responses against HER2-expressing tumours. Interestingly, although the initial immune activation mediated by the mBiNE was receptor dependent, the subsequent antitumour immunity also generated protective effects against tumour-cell populations that lacked the HER2 receptor. Thus, the mBiNE represents a new targeted, nanomaterial-immunotherapy platform to stimulate innate and adaptive immunity and promote a universal antitumour response.

Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nano-based therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications. As such, our aim in this mini-review is to discuss the current knowledge on predictive safety and structure-activity relationship (SAR) analysis of major ENMs at the developing stage, as well as the necessity of additional long-term toxicological analysis that would help to facilitate their transition into clinical practices. We focus on how the interaction of these nanomaterials with cells would trigger signaling pathways as molecular initiating events that lead to adverse outcomes. These mechanistic understandings would help to design safer ENMs with improved therapeutic efficacy in clinical settings., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Human osteopontin (OPN) is a glycosylated phosphoprotein which is expressed in a variety of tissues in the body. In recent years, accumulating evidence has indicated that the aberrant expression of OPN is closely associated with tumourigensis, progression and most prominently with metastasis in several tumour types. In this review, we present the current knowledge on the expression profiles of OPN and its main splice variants in human cancers, as well as the potential implications in patient outcome. We also discuss its putative clinical application as a cancer biomarker and as a therapeutic target.

Despite a decade of intensive preclinical research, the translation of cancer nanomedicine to the clinic has been slow. Here, we discuss how recent lessons learned from the successes with immuno-oncology therapies could be applied to cancer nanomedicine and how this may help to overcome some of the key technical challenges in this field.

Formerly known for its importance in the immune system and kidney regeneration, it is becoming more apparent that HAVcR-1 an important protein in cancer biology. HAVcR-1 is overexpressed in numerous cancers and associates with critical molecules of tight junctions. Tight junctions are critical in homeostasis of cellular compartments via the maintenance of epithelia and endothelia however it has also be suggested that via the prevention of dissemination, intravasation and extravasation, tight junctions play a critical role in the prevention of cancer metastasis. HAVcR-1 shedding and the production of the HAVcR-1 ectodomain has been linked to increased IL-6 thus implicated it in the process of angiogenesis via the activation of the STAT3 pathway leading to increased HIF-1α. The HAVcR-1 ectodomain has also been shown to be a potential urinary biomarker in certain cancers. HAVcR-1 is potentially important molecule both for the detection of cancer and the treatment of cancer by being a novel target for anti-cancer therapeutics.

Nanomedicine offers unique advantages in treating human cancers. However, physiological and pathological barriers within normal and disease tissues, which are highly variable among individuals, often hinder its effectiveness. The body possesses specific innate responses to nanoparticles (NPs), which when combined with unique pathophysiological signatures in the tumor microenvironment, can severely limit the utility of nanomedicine in the oncological setting. Furthermore, with the successes of cancer immunotherapies, understanding nanoimmune interactions and developing immune-smart cancer nanomedicine that can take advantage of the body's immune functions will increasingly become clinically relevant. Therefore, a better understanding of the important native and acquired biological processes that dictate the fate of nanomedicine is integral to developing more effective individualized platforms for treating cancer patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Carbon monoxide (CO) has always been recognised as a toxic gas, due to its higher affinity for haemoglobin than oxygen. However, biological studies have revealed an intriguing role for CO as an endogenous signalling molecule, a gasotransmitter. CO is demonstrated to exert many cellular activities including anti-inflammatory, antiapoptotic, and antiproliferative activities. In animal studies, CO gas administration can prevent tissues from hypoxia or ischemic-reperfusion injury. As a result, there are a plethora of reports dealing with the biological applications of CO and CO-releasing molecules (CORMs) in inflammatory and vascular diseases. CORMs have already been tested as a therapeutic agent in clinical trials. More recently, an increased interest has been drawn to CO's potential use as an anticancer agent. In this review, we will aim to give an overview of the research focused on the role of CO and CORMs in different types of cancer and expand to the recent development of the next generation CORMs for clinical application in cancer treatment., Competing Interests: The authors declare that they have no competing interests.