Search

Objective: Cancer patients generally have high stress levels, which often leads to depression, anxiety and other psychological problems. Laughter therapy has been used to relieve stress, depression and anxiety in cancer patients, but its efficacy is uncertain. The study aims to summarize evidence on the efficacy of laughter therapy on psychological symptoms of people with cancer., Methods: A search was conducted in 10 electronic databases for randomized controlled trials (RCTs) reported before May 2023. This systematic review was reported based on the PRISMA 2020 statement. The evaluation of methodological quality and risk of biases were conducted by the Cochrane Risk of Bias Assessment tool version 2, and evidence evaluation was conducted using the GRADE pro online assessment tool. Statistical analysis adopted the Review Manager version 5.4 software., Results: A total of eight studies were included involving 543 participants. Meta-analysis showed that laughter therapy plus routine nursing produced more positive effects than routine nursing in relieving stress (SMD = -1.18, 95% CI -1.73, -0.62, p < 0.0001), depression (SMD = -1.05, 95% CI -1.30, -0.81, p < 0.00001) and anxiety (SMD = -0.81, 95% CI -1.20, -0.43, p < 0.0001)., Conclusions: Laughter therapy could effectively relieve stress, depression and anxiety of cancer patients. Future studies should improve the methodological quality of randomized controlled trials, conduct appropriate follow-up, and report details of follow-up. Additionally, it should perform multi-center and large-sample studies, and combine both subjective and objective outcome indications to enhance the persuasiveness of evidence supporting the effectiveness of laughter therapy., Trial Registration: PROSPERO register: CRD 42023452739., (© 2024 John Wiley & Sons Ltd.)

Accumulating research showed that ENC1 plays a critical role in maintaining the physiological functions. However, little is known about its role in predicting prognosis and immunotherapy response across cancers. In our results, compared to normal tissues, most cancer tissues exhibit increased ENC1 expression. We found that the most common type of genetic variation was gene mutation. In addition, a positive correlation was found between CNV and ENC1 expression. Moreover, the overexpression of ENC1 was positively correlated with poor clinical outcomes. The GSEA results showed that ENC1 is closely correlated with tumor-promoting biological functions in most cancers. ENC1 is also closely negatively associated with the infiltration levels of T cells, activated NK cells, and B cells. Most immunomodulators are positively associated with ENC1. Further, we verified that inhibition of ENC1 expression suppressed the proliferation and migration of breast cancer, pancreatic cancer and glioma cells. In conclusion, our study demonstrated that ENC1 plays a protumorigenic role in most cancers. Additionally, ENC1 is closely correlated with tumor microenvironment features and immune checkpoint inhibitors expression. Overall, ENC1 could serve as a promising potential prognostic biomarker in various tumors., (© 2024. The Author(s).)

Background: China accounts for 24% of newly diagnosed cancer cases and 30% of cancer-related deaths worldwide. Comprehensive analyses of the economic burden on patients across different cancer treatment phases, based on empirical data, are lacking. This study aims to estimate the financial burden borne by patients and analyze the cost compositions of the leading cancers with the highest number of new cases in China., Methods: This cross-sectional cost-of-illness study analyzed patients diagnosed with lung, breast, colorectal, esophageal, liver, or gastric cancer, identified through electronic health records (EHRs) from 84 hospitals across 17 provinces in China. Patients completed any one of the initial treatment phase, follow-up phase, and relapse/metastasis phase were recruited by trained attending physicians through a stratified sampling procedure to ensure enough cases for each cancer progression stage and cancer treatment phase. Direct and indirect costs by treatment phase were collected from the EHRs and self-reported surveys. We estimated per case cost for each type of cancer, and employed subgroup analyses and multiple linear regression models to explore cost drivers., Results: We recruited a total of 13,745 cancer patients across three treatment phases. The relapse/metastasis phase incurred the highest per case costs, varying from $8,890 to $14,572, while the follow-up phase was the least costly, ranging from $1,840 to $4,431. Being in the relapse/metastasis phase and having an advanced clinical stage of cancer at diagnosis were associated with significantly higher cost, while patients with low socioeconomic status borne lower costs., Conclusions: There were substantial financial burden on patients with six leading cancers in China. Health policymakers should emphasize comprehensive healthcare coverage for marginalized populations such as the uninsured, less educated, and those living in underdeveloped regions., (© 2024. The Author(s).)

Background: Previous studies only focused on the individual social factors, without considering the overall social health patterns. The present study aimed to develop an integrated social health score (SHS) and investigate its associations with all-cause, cardiovascular disease (CVD), cancer mortality., Methods: A total of 330,716 participants (mean age 56.3 years; 52.4 % female) from UK Biobank was included between 2006 and 2010, and thereafter followed up to 2021. SHS was calculated by using information on social connections, social engagement and social support. Cox proportional hazards models was used to estimate the hazard ratios and 95 % confidence intervals (CIs) of the association between SHS and all-cause and cause-specific mortality and the 4-way decomposition was used to quantify the mediating effect of lifestyle factors., Results: During a median follow-up period of 12.4 years, 37,897 death cases were recorded, including 4347 CVD and 10,380 cancer cases. The SHS was inversely associated with the risks of all-cause, CVD and cancer mortality in a dose-dependent manner (P for trend <0.001). The association between SHS with all-cause mortality was mediated by lifestyle factors including diet score, smoking status and alcohol consumption., Conclusion: Integrated SHS was inversely associated with risks of all-cause, CVD and cancer mortality, and the associations were partially mediated by lifestyle factors. Our study highlights the importance of maintaining high levels of social health by jointly enhancing social involvement, expanding social networks, and cultivating enduring intimate relationships across the life course., 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 © 2024 Elsevier B.V. All rights reserved.)

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a potential biomarker for breast cancer (BC) diagnosis and prognosis. However, existing fluorescent probes for NQO1 detection have limitations such as short emission wavelength, weak fluorescence response, or large background interference. Here, we developed two novel near-infrared (NIR) fluorescent probes, DCl-Q and DCl 2 -Q, that selectively detect NQO1 activity in BC cells and tissues. They consist of a trimethyl-locked quinone as the recognition group and a donor-π-acceptor structure with halogen atoms as the reporter group. They exhibit strong fluorescence emission at around 660 nm upon binding to NQO1. We demonstrated that they can distinguish BC cells with different NQO1 expression levels and image endogenous NQO1 in tumor-bearing mice. Our probes provide a convenient and highly sensitive tool for BC diagnosis and prognosis based on NQO1 detection., 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 © 2024 Elsevier B.V. All rights reserved.)

Purpose: This study aims to review the multifaceted roles of a membrane protein named Fibroblast Activation Protein (FAP) expressed in tumor tissue, including its molecular functionalities, regulatory mechanisms governing its expression, prognostic significance, and its crucial role in cancer diagnosis and treatment., Methods: Articles that have uncovered the regulatory role of FAP in tumor, as well as its potential utility within clinical realms, spanning diagnosis to therapeutic intervention has been screened for a comprehensive review., Results: Our review reveals that FAP plays a pivotal role in solid tumor progression by undertaking a multitude of enzymatic and nonenzymatic roles within the tumor stroma. The exclusive presence of FAP within tumor tissues highlights its potential as a diagnostic marker and therapeutic target. The review also emphasizes the prognostic significance of FAP in predicting tumor progression and patient outcomes. Furthermore, the emerging strategies involving FAPI inhibitor (FAPI) in cancer research and clinical trials for PET/CT diagnosis are discussed. And targeted therapy utilizing FAP including FAPI, chimeric antigen receptor (CAR) T cell therapy, tumor vaccine, antibody-drug conjugates, bispecific T-cell engagers, FAP cleavable prodrugs, and drug delivery system are also introduced., Conclusion: FAP's intricate interactions with tumor cells and the tumor microenvironment make it a promising target for diagnosis and treatment. Promising strategies such as FAPI offer potential avenues for accurate tumor diagnosis, while multiple therapeutic strategies highlight the prospects of FAP targeting treatments which needs further clinical evaluation., (© 2023. Springer Nature Switzerland AG.)

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

It remains a tremendous challenge to explore effective therapeutic modalities against neuroblastoma, a lethal cancer of the sympathetic nervous system with poor prognosis and disappointing treatment outcomes. Considering the limitations of conventional treatment modalities and the intrinsic vulnerability of neuroblastoma, we herein develop a pioneering sequential catalytic therapeutic system that utilizes lactate oxidase (LOx)/horseradish peroxidase (HRP)-loaded amorphous zinc metal-organic framework, named LOx/HRP-aZIF, in combination with a 3-indole-acetic acid (IAA) prodrug. On the basis of abnormal lactate accumulation that occurs in the tumor microenvironment, the cascade reaction of LOx and HRP consumes endogenous glutathione and a reduced form of nicotinamide adenine dinucleotide to achieve the first stage of killing cancer cells via antioxidative incapacitation and electron transport chain interference. Furthermore, the generation of reactive oxygen species induced by HRP and IAA through bioorthogonal catalysis promotes ferritin degradation and lipid peroxidation, ultimately provoking self-enhanced ferroptosis with positive feedback by initiating an endogenous Fenton reaction. This work highlights the superiority of the natural enzyme-dependent cascade and bioorthogonal catalytic reaction, offering a paradigm for synergistically enzyme-based metabolism-ferroptosis anticancer therapy.

The methionine adenosyltransferase MAT2A catalyzes the synthesis ofthe methyl donor S-adenosylmethionine (SAM) and thereby regulates critical aspects of metabolism and transcription. Aberrant MAT2A function can lead to metabolic and transcriptional reprogramming of cancer cells, and MAT2A has been shown to promote survival of MTAP-deficient tumors, a genetic alteration that occurs in ∼ 13 % of all tumors. Thus, MAT2A holds great promise as a novel anticancer target. Here, we report a novel series of MAT2A inhibitors generated by a fragment growing approach from AZ-28, a low-molecular weight MAT2A inhibitor with promising pre-clinical properties. X-ray co-crystal structure revealed that compound 7 fully occupies the allosteric pocket of MAT2A as a single molecule mimicking MAT2B. By introducing additional backbone interactions and rigidifying the requisite linker extensions, we generated compound 8, which exhibited single digit nanomolar enzymatic and sub-micromolar cellular inhibitory potency for MAT2A., 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 © 2024. Published by Elsevier Ltd.)

Chemotherapy is one of the most efficient methods for treating cancer patients. Chemotherapy aims to eliminate cancer cells as thoroughly as possible. Delivering medications to patients' bodies through various methods, either oral or intravenous is part of the chemotherapy process. Different cell-kill hypotheses take into account the interactions of the expansion of the tumor volume, external drugs, and the rate of their eradication. For the control of drug usage and tumor volume, a model based smooth super-twisting control (MBSSTC) is proposed in this paper. Firstly, three nonlinear cell-kill mathematical models are considered in this work, including the log-kill, Norton-Simon, and E max hypotheses subject to parametric uncertainties and exogenous perturbations. In accordance with clinical recommendations, the tumor volume follows a predefined trajectory after chemotherapy. Secondly, the MBSSTC is applied for the three cell-kill models to attain accurate trajectory tracking even in the presence of uncertainties and disturbances. Compared to conventional super-twisting control (STC), the non-smooth term is introduced in the proposed control to enhance the anti-disturbance capability. Finally, simulation comparisons are performed across the proposed MBSSTC, conventional STC, and proportional-integral (PI) control methods to show the effectiveness and merits of our designed control method., 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cancer vaccines with the ability to elicit tumor-specific immune responses have attracted significant interest in cancer immunotherapy. A key challenge for effective cancer vaccines is the spatiotemporal codelivery of antigens and adjuvants. Herein, we synthesized a copolymer library containing nine poly(ethylene glycol) methyl ether methacrylate- co -butyl methacrylate- co -2-(azepan-1-yl)ethyl methacrylate (PEGMA- co -BMA- co -C7AMA) graft copolymers with designed proportions of different components to regulate their properties. Among these polymers, C-25, with a C7AMA:BMA ratio at 1.5:1 and PEG wt % of 25%, was screened as the most effective nanovaccine carrier with enhanced ability to induce mouse bone marrow-derived dendritic cell (BMDC) maturation. Additionally, RNA-sequencing (RNA-Seq) analysis revealed that C-25 could activate dendritic cells (DCs) through multisignaling pathways to trigger potent immune effects. Then, the screened C-25 was used to encapsulate the model peptide antigen, OVA 257-280 , to form nanovaccine C-25/OVA 257-280 . It was found that the C-25/OVA 257-280 nanovaccine could effectively facilitate DC maturation and antigen cross-presentation without any other additional adjuvant and exhibited excellent prophylactic efficacy in the B16F10-OVA tumor model. Moreover, in combination with antiprogrammed cell death protein-ligand 1 (anti-PD-L1), the C-25/OVA 257-280 nanovaccine could significantly delay the growth of pre-existing tumors. Therefore, this work developed a minimalist nanovaccine with a simple formulation and high efficiency in activating tumor-specific immune responses, showing great potential for further application in cancer immunotherapy.

Although low-cost nanozymes with excellent stability have demonstrated the potential to be highly beneficial for nanocatalytic therapy (NCT), their unsatisfactory catalytic activity accompanied by intricate tumor microenvironment (TME) significantly hinders the therapeutic effect of NCT. Herein, for the first time, a heterojunction (HJ)-fabricated sonoresponsive and NIR-II-photoresponsive nanozyme is reported by assembling carbon dots (CDs) onto TiCN nanosheets. The narrow bandgap and mixed valences of Ti 3+ and Ti 4+ endow TiCN with the capability to generate reactive oxygen species (ROS) when exposed to ultrasound (US), as well as the dual enzyme-like activities of peroxidase and glutathione peroxidase. Moreover, the catalytic activities and sonodynamic properties of the TiCN nanosheets are boosted by the formation of HJs owing to the increased speed of carrier transfer and the enhanced electron-hole separation. More importantly, the introduction of CDs with excellent NIR-II photothermal properties could achieve mild hyperthermia (43 °C) and thereby further improve the NCT and sonodynamic therapy (SDT) performances of CD/TiCN. The synergetic therapeutic efficacy of CD/TiCN through mild hyperthermia-amplified NCT and SDT could realize "three-in-one" multimodal oncotherapy to completely eliminate tumors without recurrence. This study opens a new avenue for exploring sonoresponsive and NIR-II-photoresponsive nanozymes for efficient tumor therapy based on semiconductor HJs., (© 2023 Wiley-VCH GmbH.)

Bacteria can colonize a variety of in vivo biointerfaces, particularly the skin, nasal, and oral mucosa, the gastrointestinal tract, and the reproductive tract, but also target specific lesion sites, such as tumor and wound. By virtue of their prominent characteristics in motility, editability, and targeting ability, bacteria carrying imageable agents are widely developed as living probes for bioimaging and diagnosis of different diseases. This review first introduces the strategies used for preparing bacteria-based living probes, including biological engineering, chemical modification, intracellular loading, and optical manipulation. It then summarizes the recent progress of these living probes for fluorescence imaging, near-infrared imaging, ultrasonic imaging, photoacoustic imaging, magnetic resonance imaging, and positron emission tomography imaging. The biomedical applications of bacteria-based living probes are also reviewed particularly in the bioimaging and diagnosis of bacterial infections, cancers, and intestine-associated diseases. In addition, the advantages and challenges of bacteria-based living probes are discussed and future perspectives are also proposed. This review provides an updated overview of bacteria-based living probes, highlighting their great potential as a unique yet versatile platform for developing next-generation imageable agents for intelligent bioimaging, diagnosis, and even therapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Efficiently reawakening immune cells, including T cells and macrophages, to eliminate tumor cells is a promising strategy for cancer treatment, but remains a huge challenge nowadays. Herein, a nanoassembly formed by doxorubicin (DOX)-conjugated polyphosphoester (PP-(hDOX)) and CD47-targeting siRNA (siCD47) via electrostatic and π-π stacking interactions, termed as PP-(hDOX&siCD47), was developed to reawaken the T cell and macrophage-mediated anticancer activity. The PP-(hDOX&siCD47) could efficiently blockade antiphagocytic signal by downregulation of CD47 expression to reactive macrophage-mediated anticancer immunotherapy. Moreover, the conjugated DOX of PP-(hDOX&siCD47) can perform the chemotherapy towards tumor cells and also elicit the T cell-mediated anticancer immune response via immunogenic cell death (ICD) effect. Therefore, the PP-(hDOX&siCD47) treatment could significantly increase M1-like macrophages proportion and tumor infiltration of CD8 + T cells, while the proportions of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were considerably reduced in tumor tissue, eventually achieving significantly tumor growth inhibition. Overall, this study provides a simple siRNA and DOX codelivery approach to simultaneously elicit the macrophage- and T cell-mediated anticancer immune response 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 Elsevier Ltd. All rights reserved.)

Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The heavy care burden, long-term dependence of caring for cancer patients, and changing social roles put family caregivers at high risk of mental disorders and hopelessness. This explored the relationship between fatigue, sleep quality, rumination, and hopelessness, and provides suggestions to maintain caregivers' mental health., Methods: We investigated 536 family caregivers of cancer patients in three grade A hospitals in Liaoning Province who met the inclusion criteria on the Beck Hopelessness Scale (BHS), Fatigue Scale-14 (FS-14), Nolen-Hoeksema Ruminative Responses Scale (RRS), and Pittsburgh Sleep Quality Index (PSQI). Data were analyzed with SPSS 26.0, and Amos 22.0 was used to fit the structural equation model., Results: The family caregivers had a higher degree of hopelessness and fatigue, while sleep quality and rumination were positively correlated with hopelessness (r = 0.483-0.906; P < 0.05). Fatigue and sleep quality can indirectly affect hopelessness through rumination thinking, while hopelessness has a direct effect on sleep., Conclusions: There are multiple action paths between fatigue and sleep quality, rumination thinking, and hopelessness. Family caregivers' physical and mental health can be maintained and hopelessness avoided by improving sleep quality, alleviating fatigue, and psychological counseling., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.

Drug delivery systems (DDSs) play an important role in delivering active pharmaceutical ingredients (APIs) to targeted sites with a predesigned release pattern. The chemical and biological properties of APIs and excipients have been extensively studied for their contribution to DDS quality and effectiveness; however, the structural characteristics of DDSs have not been adequately explored. Structure pharmaceutics involves the study of the structure of DDSs, especially the three-dimensional (3D) structures, and its interaction with the physiological and pathological structure of organisms, possibly influencing their release kinetics and targeting abilities. A systematic overview of the structures of a variety of dosage forms, such as tablets, granules, pellets, microspheres, powders, and nanoparticles, is presented. Moreover, the influence of structures on the release and targeting capability of DDSs has also been discussed, especially the in vitro and in vivo release correlation and the structure-based organ- and tumor-targeting capabilities of particles with different structures. Additionally, an in-depth discussion is provided regarding the application of structural strategies in the DDSs design and evaluation. Furthermore, some of the most frequently used characterization techniques in structure pharmaceutics are briefly described along with their potential future applications.

Impressive results in cancer treatment have been obtained through immunotherapy. However, abnormally high cholesterol metabolism in the tumor microenvironment (TME) leads to poor immunogenicity or even immunosuppression, which dramatically reduces the clinical response of patients with oral squamous cell carcinoma (OSCC) to immunotherapy. In this study, a cholesterol-modulating nanoplatform (PYT NP) is developed to restore the normal immune microenvironment, significantly inhibiting SQLE (an essential gene for cholesterol biosynthesis in tumor cells) by releasing terbinafine, thereby reducing cholesterol in the TME and suppressing tumor cell proliferation. In addition, the nanoplatform is equipped with a second near-infrared (NIR-II) photosensitizer, Y8, which triggers immunogenic cell death of tumor cells, thereby promoting intra-tumor infiltration and immune activation via the production of damage-associated molecular patterns for photoimmunotherapy. PYT NPs show great promise in stimulating strong cholesterol-modulating anticancer immunity combined with photoimmunotherapy, opening up a new avenue for sensitized OSCC immunotherapy., (© 2023 Wiley-VCH GmbH.)

Currently, the effectiveness of oncotherapy is limited by tumor heterogeneities, which presents a huge challenge for the development of nanotargeted drug delivery systems (DDSs). Therefore, it is important to resolve the spatiotemporal interactions between tumors and nanoparticles. However, targeting evaluation has been limited by particle visualization due to the gap between whole-organ scale and subcellular precision. Here, a high-precision three-dimensional (3D) visualization of tumor structure based on the micro-optical sectioning tomography (MOST) system and fluorescence MOST (fMOST) system is presented to clarify 3D spatial distribution of nanoparticles within the tumor. We demonstrate that through the MOST/fMOST system, it is possible to reveal multidimensional and cross-scale correlations between the tumor structure and nanoparticle distribution to remodel the tumor microenvironment and explore the structural parameters of vasculature. This visualization methodology provides an accurate assessment of the efficacy, distribution, and targeting efficiency of DDSs for oncotherapy compared to available approaches.

Therapeutics based on living organisms provide a roadmap for next-generation biomedicine. Bacteria have an essential role in the development, regulation, and treatment of gastrointestinal disease and cancer through similar mechanisms. However, primitive bacteria lack the stability to overcome complex drug delivery barriers, and their multifunctionality in reinforcing both conventional and emerging therapeutics is limited. Artificially engineered bacteria (ArtBac) with modified surfaces and genetic functions show promise for tackling these problems. Herein, we discuss recent applications of ArtBac as living biomedicine for the treatment of gastrointestinal diseases and tumors. Future perspectives are given to guide the rational design of ArtBac toward safe multifunctional medicine., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-α (IFN-α) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Autologous cancer vaccines constructed by nonproliferative whole tumor cells or tumor lysates together with appropriate adjuvants represent a promising strategy to suppress postsurgical tumor recurrence. Inspired by the potency of cytosolic double-stranded DNA (dsDNA) in initiating anticancer immunity by activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, we herein report the concise synthesis of a cGAS-STING agonist through dsDNA-templated biomineralization growth of calcium carbonate (CaCO 3 ) microparticles. The yielded DNA@CaCO 3 can activate the intracellular cGAS-STING pathway of dendritic cells (DCs) by promoting endosomal escape of dsDNA, triggering their maturation and activation as a potent immune stimulator. Upon intratumoral injection, DNA@CaCO 3 can reverse the immunosuppressive tumor microenvironment by simultaneously provoking innate and adaptive antitumor immunity, thereby effectively suppressing the growth of murine CT26 and B16-F10 tumors in mice. Furthermore, via CaCO 3 -based biomineralization of complete tumor lysates, we constructed a personalized autologous cancer vaccine with intrinsic cGAS-STING activation capacity that could provoke tumor-specific immune responses to not only delay the growth of challenged tumors but also synergize with anti-PD-1 immunotherapy to suppress postsurgical tumor recurrence. This study highlights a CaCO 3 -based biomineralization method to prepare autologous cancer vaccines in a concise manner, which is promising for personalized immunotherapy and clinical translation.

Tumour-selective theranostic agents have attracted considerable interest over the past decade in oncology owing to their extraordinary anticancer efficacy. However, it still remains a challenge to develop theranostic agents balancing biocompatibility, multidimensional theranostics, tumour-selectivity, and simple components. Inspired by the metabolic pathways of exogenous sodium selenite against selenium-deficient diseases, reported here is the first convertible bismuth-based agent for tumour-selective theranostic functionalities. The specifically overexpressed substances in tumour tissue enable it to act as a natural reactor for the conversion from bismuth selenite to bismuth selenide, activating the theranostic functionalities specifically in tumour tissues. The converted product exhibits excellent multidimensional imaging-guided therapy. This study not only demonstrates a simple agent with both biocompatibility and sophisticated tumour-selective theranostic functionalities, but also pioneers a new approach from emulating nature towards oncological theranostic applications.

Importance: Cancers are a leading cause of mortality, accounting for nearly 10 million annual deaths worldwide, or 1 in 6 deaths. Cancers also negatively affect countries' economic growth. However, the global economic cost of cancers and its worldwide distribution have yet to be studied., Objective: To estimate and project the economic cost of 29 cancers in 204 countries and territories., Design, Setting, and Participants: A decision analytical model that incorporates economic feedback in assessing health outcomes associated with the labor force and investment. A macroeconomic model was used to account for (1) the association of cancer-related mortality and morbidity with labor supply; (2) age-sex-specific differences in education, experience, and labor market participation of those who are affected by cancers; and (3) the diversion of cancer treatment expenses from savings and investments. Data were collected on April 25, 2022., Main Outcomes and Measures: Economic cost of 29 cancers across countries and territories. Costs are presented in international dollars at constant 2017 prices., Results: The estimated global economic cost of cancers from 2020 to 2050 is $25.2 trillion in international dollars (at constant 2017 prices), equivalent to an annual tax of 0.55% on global gross domestic product. The 5 cancers with the highest economic costs are tracheal, bronchus, and lung cancer (15.4%); colon and rectum cancer (10.9%); breast cancer (7.7%); liver cancer (6.5%); and leukemia (6.3%). China and the US face the largest economic costs of cancers in absolute terms, accounting for 24.1% and 20.8% of the total global burden, respectively. Although 75.1% of cancer deaths occur in low- and middle-income countries, their share of the economic cost of cancers is lower at 49.5%. The relative contribution of treatment costs to the total economic cost of cancers is greater in high-income countries than in low-income countries., Conclusions and Relevance: In this decision analytical modeling study, the macroeconomic cost of cancers was found to be substantial and distributed heterogeneously across cancer types, countries, and world regions. The findings suggest that global efforts to curb the ongoing burden of cancers are warranted.

Chemodynamic therapy (CDT) is well-known for using the tumor microenvironment to activate the Fenton reaction or Fenton-like reaction to generate strong oxidative hydroxyl radicals for tumor-specific treatment. It is highly selective and safe, without depth limitation of tissue penetration, and shows its potential as a new green therapeutic method with great clinical application. However, the catalytic efficiency of reagents involved in the Fenton reaction is severely affected by the inherent microenvironmental limitations of tumors and the strict Fenton reaction-dependent conditions. With the increasing application of nanotechnology in the medical field, combined therapies based on different types of functional nanomaterials have opened up new avenues for the development of next-generation CDT-enhanced system. This review will comprehensively exemplify representative results of combined therapies of CDT with other antitumor therapies such as chemotherapy, phototherapy, sonodynamic therapy, radiation therapy, magnetic hyperthermia therapy, immunotherapy, starvation therapy, gas therapy, gene therapy, oncosis therapy, or a combination thereof for improving antitumor efficiency from hundreds of the latest literature, introduce strategies such as the ingenious design of nanomedicines and tumor microenvironment regulations to enhance the combination therapy, and further summarize the challenges and future perspective of CDT-based multimodal anticancer therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Obesity usually induces systemic metabolic disturbances, including in the tumor microenvironment (TME). This is because adaptive metabolism related to obesity in the TME with a low level of prolyl hydroxylase-3 (PHD3) depletes the major fatty acid fuels of CD8 + T cells and leads to the poor infiltration and unsatisfactory function of CD8 + T cells. Herein, we discovered that obesity could aggravate the immunosuppressive TME and weaken CD8 + T cell-mediated tumor cell killing. We have thus developed gene therapy to relieve the obesity-related TME to promote cancer immunotherapy. An efficient gene carrier was prepared by modifying polyethylenimine with p -methylbenzenesulfonyl (abbreviated as PEI-Tos) together with hyaluronic acid (HA) shielding, achieving excellent gene transfection in tumors after intravenous administration. H A/ P EI-Tos/ p D NA ( HPD ) containing the plasmid encoding PHD3 ( p PHD3) can effectively upregulate the expression of PHD3 in tumor tissues, revising the immunosuppressive TME and significantly increasing the infiltration of CD8 + T cells, thereby improving the responsiveness of immune checkpoint antibody-mediated immunotherapy. Efficient therapeutic efficacy was achieved using HPD together with αPD-1 in colorectal tumor and melanoma-bearing obese mice. This work provides an effective strategy to improve immunotherapy of tumors in obese mice, which may provide a useful reference for the immunotherapy of obesity-related cancer in the clinic.

Photosensitizer-based therapy often suffers from unitary and easily attenuated photosensitive effects, limited tumor penetration and retention, and requirement of multiple irradiation for combination therapy, which largely restrict its application. Here, bacteria are integrated with a monochromatic irradiation-mediated ternary combination of photosensitizers for photoacoustic imaging-guided synergistic photothermal therapy. Bacteria that are bioengineered to express natural melanin are decorated with dual synthetic photosensitizers by nanodeposition with indocyanine green and polydopamine under a cytocompatible condition. The combined photosensitizers, which share an adequate excitation at 808 nm, endow integrated bacteria with a stable triple photoacoustic and photothermal effect under a monochromatic irradiation. Due to their living characteristics, these bacteria preferentially colonize hypoxic tumor tissue with homogeneous distribution and durable retention and generate uniform imaging signals and a sufficient heating of tumor upon laser irradiation. Supported by significantly inhibited tumor growth and extended survival of animals in different tumor-bearing murine models, our work proposes the development of bacteria-based innovative photosensitizers for imaging-guided therapy.

Importance: Individuals with prediabetes have a higher risk of death than healthy individuals. However, previous findings have suggested that individuals with reversion from prediabetes to normoglycemia may not have a lower risk of death compared with individuals with persistent prediabetes., Objectives: To investigate the associations between changes in prediabetes status and risk of death and to elucidate the roles of modifiable risk factors in these associations., Design, Setting, and Participants: This population-based prospective cohort study used data from 45 782 participants with prediabetes from the Taiwan MJ Cohort Study who were recruited between January 1, 1996, and December 31, 2007. Participants were followed up from the second clinical visit to December 31, 2011, with a median (IQR) follow-up of 8 (5-12) years. Participants were categorized into 3 groups according to changes in their prediabetes status within a 3-year period after initial enrollment: reversion to normoglycemia, persistent prediabetes, and progression to diabetes. Cox proportional hazards regression models were used to examine the associations between changes in prediabetes status at baseline (ie, the second clinical visit) and risk of death. Data analysis was performed between September 18, 2021, and October 24, 2022., Main Outcomes and Measures: All-cause mortality, cardiovascular disease (CVD)-related mortality, and cancer-related mortality., Results: Of 45 782 participants with prediabetes (62.9% male; 100% Asian; mean [SD] age, 44.6 [12.8] years), 1786 (3.9%) developed diabetes and 17 021 (37.2%) reverted to normoglycemia. Progression from prediabetes to diabetes within a 3-year period was associated with higher risks of all-cause death (hazard ratio [HR], 1.50; 95% CI, 1.25-1.79) and CVD-related death (HR, 1.61; 95% CI, 1.12-2.33) compared with persistent prediabetes, while reversion to normoglycemia was not associated with a lower risk of all-cause death (HR, 0.99; 95% CI, 0.88-1.10), cancer-related death (HR, 0.91; 95% CI, 0.77-1.08), or CVD-related death (HR, 0.97; 95% CI, 0.75-1.25). Among individuals who were physically active, reversion to normoglycemia was associated with a lower risk of all-cause death (HR, 0.72; 95% CI, 0.59-0.87) compared with those with persistent prediabetes who were physically inactive. Among individuals with obesity, risk of death varied between those who experienced reversion to normoglycemia (HR, 1.10; 95% CI, 0.82-1.49) and those who had persistent prediabetes (HR, 1.33; 95% CI, 1.10-1.62)., Conclusions and Relevance: In this cohort study, although reversion from prediabetes to normoglycemia within a 3-year period did not mitigate the overall risk of death compared with persistent prediabetes, risk of death associated with reversion to normoglycemia varied based on whether individuals were physically active or had obesity. These findings highlight the importance of lifestyle modification among those with prediabetes status.

Chirality is ubiquitous in biological systems, which is closely related to biological functions, life processes, and even the pathogenesis of diseases. However, the interface between the chirality of synthetic materials and organisms, particularly the immune system, remains poorly understood. Here, supramolecular chiral polymer micelles (SCPMs) are prepared by complexing antigenic proteins with chiral amino acid-modified polyethyleneimine. The introduction of chirality not only reduces the toxicity of cationic polymer, but also benefits cell uptake and antigen presentation. Especially, D-chirality presents the lowest cytotoxicity, while promoting the highest expression level of costimulatory molecules on dendritic cells compared to L-chirality and achirality. The superiority of D-chirality to stimulate dendritic cell maturation is supported by immunization with D-SCPMs, which achieves significant antigen-specific proliferation of T cells in the spleen, lymph nodes, and tumor of mice. Chirality-mediated antigen processing and presentation are demonstrated by D-SCPMs self-assembled from chiral alkaline histidine or neutral phenylalanine modified polyethyleneimine and tumor associated ovalbumin or severe acute respiratory syndrome coronavirus 2 spike 1 antigenic protein. Immunoactivation enabled by D-chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment., (© 2022 Wiley-VCH GmbH.)

Background: Only a subset of B-cell lymphoma (BCL) patients can benefit from immune checkpoint inhibitors targeting PD-1/PD-L1. Materials & methods: In the A20 model, SIRPα-Fc and anti-PD-L1 were employed to target CD47 and PD-L1 simultaneously. Flow cytometry, immunofluorescence and quantitative polymerase chain reaction were used to unravel the potential mechanisms. Results: Simultaneously targeting CD47 and PD-L1 activated CD8 + T cells with an increased release of effector molecules. Furthermore, infiltration of F4/80 + iNOS + M1 macrophages was enhanced by the dual therapy. Conclusion: Anti-CD47 therapy could sensitize BCL tumors to anti-PD-L1 therapy in a CD8 + T-cell- and M1-macrophage-dependent manner by promoting cytotoxic lymphocyte infiltration, which may provide a potential strategy for BCL treatment by simultaneously targeting CD47 and PD-L1.

The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms, including the hijacking of the tumor suppressors p53 and PP2A. Targeting aberrant SET represents a promising strategy for cancer intervention. However, the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown. Here, we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells. In addition, p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET, whereby SET-mediated inhibition of PP2A was alleviated. Moreover, targeting the interaction between SET and PP2A catalytic subunit (PP2Ac) with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55 (Thr55). Therefore, our findings uncovered a previously unknown p53-SET-PP2A regulatory feedback loop. To functionally potentiate this feedback loop, we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression. Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop., (© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The pursuit of easy-to-use, non-invasive and inexpensive diagnostics is an urgent task for clinicians and scientists. Saliva is an important component of body fluid with regular changes of contents under various pathophysiological conditions, and the biomarkers identified from saliva shows high application potentials and values in disease diagnostics. This review introduces the latest developments in saliva research, with an emphasis on the detection and application of salivary biomarkers in cancer detection., Areas Covered: Detection of disease-specific biomarkers in saliva samples by existing salivaomic methods can be used to diagnose various human pathological conditions and was introduced in details. This review also covers the saliva collection methods, the analytical techniques as well as the corresponding commercial products, with an aim to describe an holistic process for saliva-based diagnostics., Expert Opinion: Saliva, as a non-invasive and collectable body fluid, can reflect the pathophysiological changes of the human body to a certain extent. Identification of reliable saliva biomarkers can provide a convenient way for cancer detection in clinical applications.

A series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1∼Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC 50 values below 20 nM. As a highly potent ALK inhibitor (ALK WT , IC 50  = 1.6 nM), Y28 was also capable of suppressing ALK-resistant mutations including ALK L1196M (0.71 nM) and ALK G1202R (1.3 nM). Intriguingly, Y28 turned out to effectively inhibit colony formation and restrain cell migration of H2228 cells in a dose dependent manner. In addition, flow cytometric analysis indicated that Y28 could induce cell apoptosis and achieve cell cycle arrest in G2 phase. Notably, oral administration of Y28 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 70.46%. Finally, the binding models of Y28 with ALK WT & ALK G1202R within the active site well established its mode of action and accounted for the superior activities as a promising antitumor candidate., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Four pairs of undescribed enantiomeric isoquinoline alkaloids (6S/R-(N,N-diethylacetamido)yl-dihydrochelerythrine, 6R/S-acetonyl-9-hydroxy-dihydrochelerythrine, 6S/R-acroleinyl-dihydrochelerythrine, 6S/R-acetatemethyl-dihydrochelerythrine), five undescribed isoquinoline alkaloids (6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-hydroxy-dihydrochelerythrine, 9-methoxy-10-hydroxy-norchelerythrine, chelidoniumine A), together with 13 known isoquinoline alkaloids were isolated from an extract of the roots and rhizomes of Hylomecon japonica. The structures of the undescribed compounds were identified by NMR, HRESIMS, UV, IR, and their absolute configurations were defined via electronic circular dichroism data and optical rotation. All of the isolated compounds were tested for their anti-breast cancer activities in MCF-7 cells. Among them, the undescribed alkaloids 6S/R-acroleinyl-dihydrochelerythrine, 6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-methoxy-10-hydroxy-norchelerythrine and other known alkaloids 6-methoxydihydrosanguinarine, 6-acetaldehyde-dihyrochelerythrine, dihydrosanguinaline and 10-methoxy boconoline had good inhibitory effects on MCF-7 cells of breast cancer with an IC 50 lower than 20 μM., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Although therapeutic antibodies against immune checkpoints such as PD-1/PD-L1 have achieved unprecedented success in clinical tumor patients, there are still many patients who are ineffective or have limited responses to immune checkpoint blockade (ICB). Discovery of novel strategies for cancer immunotherapy including natural small molecules is needed., Methods: Owing to its extremely low content in Epimedium genus, we firstly constructed a microbial cell factory to enzymatically biosynthesize icariside I, a natural flavonoid monosaccharide from Herbal Epimedium. Using a combination of targeted MS-based metabolomics, flow cytometric analysis, and biological assays, the therapeutic potentials of icariside I were subsequently investigated in vivo and in vitro., Results: We find that icariside I markedly downregulates a series of intermediate metabolites such as kynurenine, kynurenic acid and xanthurenic acid and corresponding key enzymes involved in kynurenine-AhR pathway in both tumor cells and tumor-bearing mice. In vivo, oral administration of icariside I downregulates SLC7A8 and PAT4 transporters and AhR, thus inhibiting nuclear PD-1 in CTLs. Moreover, icariside I significantly upregulates CD8 + T cells in both peripheral blood and tumor tissues of tumor-bearing mice. Consequently, interferon-γ (IFN-γ) secreted by CD8 + T cells suppresses tumor growth through activation of JAK1-STAT1 signaling, thus inducing tumor cell apoptosis., Conclusions: These results suggest that icariside I could be an effective small molecule drug for tumor immunotherapy by blocking kynurenine-AhR pathway and tumor immune escape., Competing Interests: Conflict of interest statement The authors declare no competing financial interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The purpose of this study is to understand the cognition and experience of oncology nurses in China when responding to a patient's request to hasten death, to describe the obstacles that prevent their response, and to provide suggestions for dealing with the patient's request., Methods: Researchers conducted a qualitative study that consisted of open-ended, semi-structured interviews with 18 registered nurses who had more than 5 years of working experience in the oncology department at a large-scale urban hospital. We analyzed these data for content and themes., Results: How to deal with patients' requests to hasten death is a problem often encountered and handled by nurses in the Department of Oncology. Nurses have a certain understanding of the patients' requests to hasten death. This study abstracts four themes: (1) the nurses' cognition of the "Accelerate the process of death"; (2) the methods they use to deal with the patients' requests to hasten death; (3) the obstacles that prevent nurses from fulfilling the patients' requests to hasten death; and (4) their suggestions for improvement., Conclusion: Nurses have a deep understanding of the real thoughts of patients who make a death request, and they hope to provide the corresponding psychological support and physical care. However, the lack of relevant knowledge, policy support, and cooperation of patients' families are obstacles that prevent them from taking action. Therefore, increasing relevant training for nurses, encouraging multi-department cooperation, and developing standardized nursing processes may lay a foundation for oncology nurses to better undertake and guide such conversations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aminopeptidase N, as a target for drug discovery, shows marked relationships with many diseases, especially liver injury and cancer. Here, we explored a chemiluminescence (CL) probe for sensing APN by tethering the APN-specific substrate group to the ortho-acrylated phenoxy-dioxetane scaffold. In this way, two CL probes (APN-CL and BAPN-CL) were designed with noncapped leucine and butoxy-carbonyl capped leucine as the protecting group to preserve the chemiexcitation energy. The uncovered leucine was demonstrated to be essential for detection of APN activity by comparing the CL intensity of two CL probes. Probe APN-CL was turned on upon APN cleavage, resulting in a high chemiluminescent emission, whereas the chemiexcitation energy of probe BAPN-CL was still restrained even with the high-level APN. The result was further elucidated by molecular docking simulations. Probe APN-CL exhibited a fast response and high sensitivity with a detection limit of 0.068 U/L, and an excellent specificity for the discrimination of APN from biological ions, small molecules, and other proteases commonly found in living system. By virtue of good stability and cell viability, probe APN-CL imaged abnormal levels of APN in tumour cells and tumour-bearing mice. Moreover, this probe APN-CL could be easily used to evaluate APN inhibitors and APN levels in plasma samples from 20 patients. Overall, as a facile and cost-effective probe, APN-CL will be a promising alternative in the early diagnosis of pathologies and for cost-effective screening of inhibitors., (© 2022 John Wiley & Sons Ltd.)

Sonodynamic therapy (SDT) and photothermal therapy (PTT) are two effective strategies for the treatment of atherosclerotic plaques. However, the low yield of reactive oxygen species (ROS) of conventional organic sonosensitizers and the low biosafety of hyperthermia limit the therapeutic efficacy of SDT and PTT. Herein, we report copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for low-intensity sonodynamic and mild-photothermal synergistic therapy for early atherosclerotic plaques. CuS/TiO 2 heterostructure nanosheets (HNSs) show high electron-hole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band. Moreover, HNSs exhibit intense absorbance in the NIR-II region, which endows the nanosheets with excellent photothermal performance. With a further modification of HA, HA-HNSs can selectively target intraplaque proinflammatory macrophages through CD44-HA interaction. Because SDT reduces the expression of heat shock protein 90 and PTT facilitates the sonocatalytic process, the combination of SDT and PTT based on HA-HNSs could synergistically induce proinflammatory macrophage apoptosis. More importantly, the synergistic therapy prevents the progression of early atherosclerotic plaque by removing lesional macrophages and mitigating inflammation. Taken together, this work provides a macrophage-targeting sonodynamic/photothermal synergistic therapy, which is an effective translational clinical intervention for early atherosclerotic plaques.

Nanoparticle drug delivery is largely restricted by the low drug loading capacity of nanoparticle carriers. To address this critical challenge and maximize the potential of nanoparticle drug delivery, a 2D ultra-thin layered double hydroxide (LDH) nanosheet with exceptionally high drug loading, excellent colloidal stability, and prolonged blood circulation for cancer treatment is constructed. The nanosheet is synthesized via a biocompatible polymer-assisted bottom-up method and exhibits an ultra-thin 2D sheet-like structure that enables a considerable amount of cargo anchoring sites available for drug loading, leading to an extraordinary 734% (doxorubicin/nanoparticle mass ratio) drug loading capacity. Doxorubicin delivered by the nanosheet remains stable on the nanosheet carrier under the physiological pH condition, while showing sustained release in the tumor microenvironment and the intracellular environment, thus demonstrating on-demand drug release as a result of pH-responsive biodegradation of nanosheets. Using in vitro and in vivo 4T1 breast cancer models, the nanosheet-based ultra-high drug-loading system demonstrates even enhanced therapeutic performance compared to the multilayered LDH-based high drug-loading system, in terms of increased cellular uptake efficiency, prolonged blood circulation, superior therapeutic effect, and reduced systemic toxicity., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy., (© 2022. The Author(s).)

Purpose: To explore relationships between biological gene expression signatures and pembrolizumab response., Experimental Design: RNA-sequencing data on baseline tumor tissue from 1,188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of 11 prespecified gene expression signatures [18-gene T-cell-inflamed gene expression profile (TcellinfGEP), angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell (gMDSC), monocytic myeloid-derived suppressor cell (mMDSC), stroma/epithelial-to-mesenchymal transition (EMT)/TGFβ, and WNT] were evaluated for their relationship to objective response rate (per RECIST, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and TcellinfGEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the TcellinfGEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-TcellinfGEP consensus signatures for negative association [except proliferation (hypothesized positive association)] with response was adjusted for multiplicity., Results: Covariance patterns of the 11 signatures (including TcellinfGEP) identified in Merck-Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA-sequencing data from pembrolizumab trials. TcellinfGEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGFβ were negatively associated with response to pembrolizumab monotherapy., Conclusions: These findings suggest that features beyond IFNγ-related T-cell inflammation may be relevant to anti-programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations. See related commentary by Cho et al., p. 1479., (©2021 The Authors; Published by the American Association for Cancer Research.)

Glial cell line-derived neurotrophic factor family receptor alpha (GFRα) members have been widely connected to the mechanisms contributing to cell growth, differentiation, cell migration and tissue maturation. Here we review GFRα biological functions and discussed the evidence indicating whether GFRα signaling complex present novel opportunities for oncogenic intervention and treatment resistance. Thus, our work systematically reviewed the emerging role of GFRα family members in cancers, and provided novel insights for further researches., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Methods capable of distributing antitumor therapeutics uniformly and durably throughout an entire tumor would be of great significance in maximizing their treatment efficacy, but they have proven to be extremely challenging. Here, bacteria-mediated spatiotemporally controllable distribution of combination therapeutics in solid tumors is reported to reprogram the immune microenvironment for optimizing antitumor efficacy. By combining synthetic biology and interfacial chemistry, bacteria are inside and outside concurrently modified to express photothermal melanin and to attach immune checkpoint inhibitors on their surface. Due to the nature of bacteria to colonize the hypoxia intratumoral environment, both therapeutic agents can be distributed homogenously and lastingly in tumors during ex vivo human and in vivo mouse studies. Spatiotemporally controllable localization of melanin can repeatedly generate a moderate yet uniform heating of the tumor upon light exposure in a broad treatment window. Combination with similarly localized inhibitors elicits a dual photothermally stimulated and checkpoint-blockade-mediated immune activation effect, synergistically reprogramming the immunosuppressive tumor microenvironment. Therapeutic values are demonstrated by significantly inhibited tumor growth and prolonged survival of mice in both subcutaneous and orthotopic murine models. Colonization of dually modified bacteria paves an avenue for spatiotemporally controllable distribution of therapeutic drugs in solid tumors., (© 2021 Wiley-VCH GmbH.)

Increasing evidence indicates that cancer stem cells (CSCs) are initiators of the occurrence, development, and recurrence of malignant tumors. Mitochondria are important organelles in eukaryotic cells, not only responsible for converting part of energy released during nutrients oxidation into the energy-yielding molecule adenosine triphosphate (ATP) to fuel the activities of cell, but also play essential roles in processes such as cell apoptosis and cellular proliferation. The mitochondrial-related abnormalities have also been considered to have an important role in the origin and development of tumors. This study aimed at testing the abnormalities in mitochondrial function and energy/metabolism-related phenotypes in thyroid cancer stem cells (TCSCs). TCSCs were isolated and identified from MDA-T32 thyroid carcinoma cell line. The mitochondrial mass and mitochondrial arrangement, amount of mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), oxygen/glucose consumption, and intracellular concentrations of reactive oxygen species (ROS) and ATP levels were examined. Perinuclear mitochondrial distribution, low amount of mtDNA and oxygen/glucose consumption, high MMP, and low intracellular ROS and ATP concentrations were observed in TCSCs. Alterations in mitochondrial function and cellular energy metabolism may be used as novel indicators of thyroid cancer.

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.

Despite bacterial-mediated biotherapies have been widely explored for treating different types of cancer, their implementation has been restricted by low treatment efficacy, due largely to the absence of tumor-specific accumulation following administration. Here, the conjugation of aptamers to bacterial surface is described by a simple and cytocompatible amidation procedure, which can significantly promote the localization of bacteria in tumor site after systemic administration. The surface density of aptamers can be easily adjusted by varying feed ratio and the conjugation is able to increase the stability of anchored aptamers. Optimal bacteria conjugated with an average of 2.8 × 10 5 aptamers per cell present the highest specificity to tumor cells in vitro, separately generating near 2- and 4-times higher accumulation in tumor tissue at 12 and 60 hours compared to unmodified bacteria. In both 4T1 and H22 tumor-bearing mouse models, aptamer-conjugated attenuated Salmonella show enhanced antitumor efficacy, along with highly activated immune responses inside the tumor. This work demonstrates how bacterial behaviors can be tuned by surface conjugation and supports the potential of aptamer-conjugated bacteria for both targeted intratumoral localization and enhanced tumor biotherapy., (© 2021. The Author(s).)

Near-infrared-II (NIR-II) cancer photothermal therapy (PTT) has become more and more attractive as the NIR-II light shows a higher tissue penetrating depth, which leads to better anti-cancer effects. Recently, the members of the MXene family have been reported as NIR-II photothermal agents, possessing a high specific surface area and a fascinating light-to-heat conversion rate at the same time. Herein, we reported a combination of NIR-II photothermal therapy and immune therapy based on the MXene family member niobium carbide (Nb 2 C). First, Nb 2 C nanosheets (NSs) under 50 nm were prepared. They showed a high photothermal conversion efficiency under a 1064-nm laser, and the NIR-II light showed a deeper tissue penetration depth. Then, a nanoplatform with high R837 stability and a high loading rate was obtained after modification with a polydopamine (PDA) layer on the surface of Nb 2 C. With the R837 modification, the percentage of mature dendritic cells (DCs) increased and the immune response enhanced, compared with the immune response caused by PTT only. Finally, a red blood cell (RBC) membrane was applied as a coat over the nanoplatform in order to avoid excessive blood clearance. During in vivo experiments, blood circulation of Nb 2 C@PDA-R837@RBC nanoparticles (NPs) was prolonged, and all primary tumors were eliminated. Secondary tumors were also inhibited effectively due to the strengthened immune response, proving that Nb 2 C@PDA-R837@RBC NPs could inhibit tumor recurrence. All the results above indicated Nb 2 C@PDA-R837@RBC NPs as a potential RBC camouflaged nanoplatform for the combination of effective PTT and immune therapy towards tumor treatment.

Immunotherapy has revolutionised cancer treatment through restoration of host antitumour immune response. Immune checkpoint inhibitors (ICIs) confer durable responses in only a subset of patients. Mechanisms of ICI resistance to improve durable response rates and overall survival are an area of intense clinical research. Robust clinical development is ongoing to evaluate novel combination therapies to overcome ICI resistance, including targeting immunoregulatory pathways in the tumour microenvironment. Intratumoural (IT) immunotherapies such as toll-like receptor agonists, stimulator of interferon-induced gene agonists, retinoic-inducible gene I-like receptor agonists and oncolytic viruses may represent potential combination treatment options to overcome ICI resistance. Use of IT immunotherapies in combination with ICIs may alter the tumour microenvironment to address resistance mechanisms and improve antitumour response. Optimisation of IT immunotherapy clinical trials will elucidate resistance mechanisms, facilitate clinical trial design, define pharmacodynamic predictors that identify patients who may most benefit and inform clinical development of combination immunotherapy regimens. Here we provide an overview of IT immunotherapy principles, mechanisms of action, categories of IT immunotherapeutics, emerging data, clinical development strategies, response assessment, dose and schedule determination, clinical trial design and translational study design., Competing Interests: Conflict of interest statement J.Y. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A.K. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA. J.B. reports grants and others from Acerta, Celgene, Genentech, Kite/Gilead and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. R.H.I.A is an employee of Seven and Eight Biopharmaceuticals Inc and reports personal fees from Aduro, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Moderna Therapeutics, Novartis, Oncosec, Pfizer, Pulse Biosciences and Takara. S.H.-L. reports no conflicts of interest. J.J.L. reports scientific advisory board from 7 Hills, Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, Onc.AI, Pyxis, Spring Bank and Tempest; consultancy from AbbVie, Algios, Array, Bayer, Bristol Myers Squibb, CStone, Eisai, EMD Serono, Janssen, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Mersana, Novartis, PTx, RefleXion, Regeneron, Rubius, Silicon, Tesaro and Xilios; research support (to his institution for clinical trials unless noted) from AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol Myers Squibb, Corvus, EMD Serono, Immatics, Incyte, Kadmon, MacroGenics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Spring Bank, Tizona and Xencor; travel from Bristol Myers Squibb, EMD Serono, Janssen, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Mersana and Pyxis; patents (both provisional): Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). A.D. reports consulting fees from Apexigen, Idera and Nektar; and institutional research funding from Apexigen, Idera Pharmaceuticals, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Nektar Therapeutics. A.M. reports no conflict of interest. A.S. is an employee and stockholder of Two River, Inc. Z.A.C is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA, and in Bristol Myers Squibb. F.S.H. reports grants, personal fees, and others from Bristol Myers Squibb; personal fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and from EMD Serono; grants, personal fees and others from Novartis; personal fees from Surface, Compass Therapeutics, Apricity, Aduro, Sanofi, Pionyr, Torque, Rheos, Kairos, Bicara, Eisai, Idera, Takeda; and others from Pieris Pharmaceutical and from Corner Therapeutics. In addition, Dr. Hodi has the following patents: ‘Methods for Treating MICA-Related Disorders’ (#20100111973) with royalties paid, ‘Tumor Antigens and Uses Thereof’ (#7250291) issued, ‘Angiopoietin-2 Biomarkers Predictive of Anti-Immune Checkpoint Response’ (#20170248603) pending, ‘Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma Using PD-L1 Isoforms’ (#20160340407) pending, ‘Therapeutic Peptides’ (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, ‘Therapeutic Peptides’ (#20170008962) pending, ‘Therapeutic Peptides’ issued (#9402905), ‘Methods of Using Pembrolizumab and Trebananib’ pending, ‘Vaccine Compositions and Methods for Restoring NKG2D Pathway Function Against Cancers’ issued (#10279021), ‘Antibodies That Bind to MHC Class I Polypeptide-Related Sequence A’ issued (#10106611) and ‘Únti-Galectin Antibody Biomarkers Predictive of Anti-Immune Checkpoint and Anti-Angiogenesis Responses’ pending (#20170343552)., (Copyright © 2021 Merck Sharp & Dohme Corp. and the Author(s). Published by Elsevier Ltd.. All rights reserved.)