Strategy For Cancer Treatment Research Articles

Treatment strategies for advanced and recurrent endometrial cancer using immune checkpoint inhibitors.

Doxorubicin + cisplatin and paclitaxel + carboplatin are standard chemotherapy regimens for endometrial cancer. The development of PD-1 and PDL-1 antibody drugs has led to the use of these agents for endometrial cancer in other countries. The KEYNOTE-775 trial for advanced or recurrent endometrial cancer demonstrated the benefits of pembrolizumab and lenvatinib combination therapy, and the results of this trial led to the approval of its coverage for recurrent cancer by the Japanese health insurance system. Currently, treatment with immune checkpoint inhibitors is transitioning from second-line to first-line therapy. In a global randomized phase III study, the drugs dostarlimab, durvalumab, and atezolizumab, which are not yet approved in Japan, showed better results in the study arms than in the control arm. Additionally, biomarkers have been developed for endometrial cancer, enabling gynecologists to pursue treatment options based on the biomarkers detected for better treatment outcomes. In this article, we review the clinical trials of immune checkpoint inhibitors for advanced or recurrent endometrial cancer.

Exploring the role of the gut microbiome in modulating response to anti-PD-1 immunotherapy in melanoma patients

The gut microbiome plays a crucial role in modulating the immune response to cancer immunotherapies, particularly anti-PD-1 inhibitors, which have revolutionized the treatment of melanoma. Despite the success of these therapies in some patients, the response remains highly variable. Recent studies suggest that the composition and diversity of the gut microbiome can influence the efficacy of anti-PD-1 therapy by shaping systemic immunity, particularly through its effects on T-cell activation and tumor microenvironment dynamics. Specific microbial species, such as Akkermansia muciniphila and Bifidobacterium, as well as microbial metabolites like short-chain fatty acids (SCFAs), have been associated with enhanced immune responses and improved treatment outcomes. Conversely, dysbiosis, or microbial imbalance, has been linked to resistance to immunotherapy. This review explores the mechanisms by which the microbiome influences immune responses and discusses strategies such as fecal microbiota transplantation (FMT), dietary interventions, and probiotics to modulate the microbiome and enhance melanoma treatment outcomes. Understanding the microbiome's role in immunotherapy could lead to more personalized, effective treatment strategies for melanoma and other cancers.

Revisiting the safety limit in magnetic nanoparticle hyperthermia: insights from eddy current induced heating

Abstract Objective. 
Magnetic nanoparticle hyperthermia (MNH) emerges as a promising therapeutic strategy for cancer treatment, leveraging alternating magnetic fields (AMFs) to induce localized heating through magnetic nanoparticles (MNPs). However, the interaction of AMFs with biological tissues leads to non-specific heating caused by eddy currents, triggering thermoregulatory responses and complex thermal gradients throughout the body of the patient. While previous studies have implemented the Atkinson-Brezovich limit to mitigate potential harm, recent research underscores discrepancies between this threshold and clinical outcomes, necessitating a re-evaluation of this safety limit. Therefore, in this study, through electromagnetic (EM) simulations, the complex interaction between AMFs and anatomical models was investigated. 
Approach. 
In particular, we considered a circular coil configuration placed at different positions along the craniocaudal axis of various anatomical human models. The excitation current was normalized, at different frequencies, to meet the basic restriction of local 10g-averaged specific energy absorption rate (SAR) in the human models, as defined by the exposure guidelines of the International Commission on Non-Ionizing Radiation Protection (ICNIRP 2020) and the standard IEC 60601-2-33 of the International Electrotechnical Commission (IEC 2022). 
Main Results. 
The resulting permissible magnetic field strength values for the reference levels set by ICNIRP (2020) for occupational and general public exposure, emerged to be up to approximately 1.4 and 3 times less than that defined in the Atkinson-Brezovich limit. The widely used limit was found to align more closely with the first level of controlled operating mode defined in IEC 60601-2-33 (IEC 2022). 
Significance. 
The results indicate that the permissible magnetic field amplitude during MNH treatment should be much lower than that in the Atkinson-Brezovich limit. This study offers valuable insights into the role of computational simulations in advancing the potential to establish a reliable metric for safety evaluation and monitoring within the clinical framework of MNH.

Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy

Genomic integrity is critical for cellular homeostasis, preventing the accumulation of mutations that can drive diseases such as cancer. Among the mechanisms safeguarding genomic stability, the Base Excision Repair (BER) pathway plays a pivotal role in counteracting oxidative DNA damage caused by reactive oxygen species. Central to this pathway are enzymes like 8-oxoguanine glycosylase 1 (OGG1), which recognize and excise 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) lesions, thereby initiating a series of repair processes that restore DNA integrity. BER inhibitors have recently been identified as a promising approach in cancer therapy, increasing the sensitivity of cancer cells to radiotherapy and chemotherapy. By exploiting tumor-specific DNA repair dependencies and synthetic lethal interactions, these inhibitors could be used to selectively target cancer cells while sparing normal cells. This review provides a robust reference for scientific researchers, offering an updated perspective on small-molecule inhibitors targeting the 8-oxodG-BER pathway and highlighting their potential role in expanding cancer treatment strategies.

Exploration of Novel Therapeutic Targets for Breast Carcinoma and Molecular Docking Studies of Anticancer Compound Libraries with Cyclin-dependent Kinase 4/6 (CDK4/6): A Comprehensive Study of Signalling Pathways for Drug Repurposing.

This study aims to identify and evaluate promising therapeutic proteins and compounds for breast cancer treatment through a comprehensive database search and molecular docking analysis. Breast cancer (BC), primarily originating from the terminal ductal-lobular unit of the breast, is the most prevalent form of cancer globally. In 2020, an estimated 2.3 million new cases were reported, resulting in approximately 685,000 deaths. Mutations in the BRCA1 and BRCA2 genes are well-established in hereditary breast cancer. The identification of effective therapeutic proteins for BC remains a complex and evolving area of research. This study aims to identify and evaluate promising therapeutic proteins and compounds specific to breast cancer through a comprehensive database search and molecular docking analysis. A rigorous search was conducted within the National Cancer Institute (NCI), NCI Metathesaurus, SIGnaling Network Open Resource (SIGNOR), Human Protein Atlas (HPA), and the Human Phenotype Ontology (HPO) to shortlist proteins linked to BC (CUI C0678222). Recent studies were reviewed to understand the administration of CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) combined with endocrine therapy for HR-positive and HER2-negative breast cancer. Anticancer compound libraries available at ZINC and PubChem were analyzed. Compounds were evaluated based on their binding energies with CDK4 protein, a rationally selected druggable target. Key proteins linked to breast cancer were identified through database searches. Proliferation, apoptosis, and G1/S transition pathways were frequently found dysregulated in breast cancer. ZINC13152284 exhibited the strongest binding energy at -10.9 Kcal/mol, followed by ZINC05492794 with a binding energy of -10.4 Kcal/mol. Preexisting drugs showed lower binding energies with the CDK4 protein. The study highlights the importance of drug repurposing as a strategy for the safe and effective treatment of breast cancer. Synthetic inhibitors often cause severe side effects, emphasizing the need for novel targets and compounds with better therapeutic profiles. Molecular docking identified promising compounds from the ZINC database, suggesting potential new avenues for breast cancer therapy.

N6-methyladenosine RNA modification regulates the transcription of SLC7A11 through KDM6B and GATA3 to modulate ferroptosis

BackgroundRecent studies indicate that N6-methyladenosine (m6A) RNA modification may regulate ferroptosis in cancer cells, while its molecular mechanisms require further investigation.MethodsLiquid Chromatography-Tandem Mass Spectrometry (HPLC/MS/MS) was used to detect changes in m6A levels in cells. Transmission electron microscopy and flow cytometry were used to detect mitochondrial reactive oxygen species (ROS). RNA sequencing (RNA-seq) was employed to analyze the factors regulating ferroptosis. Chromatin immunoprecipitation (ChIP) was used to assess the binding of regulatory factors to the SLC7A11 promoter, and a Dual-Luciferase reporter assay measured promoter activity of SLC7A11. The dm6ACRISPR system was utilized for the demethylation of specific transcripts. The Cancer Genome Atlas Program (TCGA) database and immunohistochemistry validated the role of the METTL3/SLC7A11 axis in cancer progression.ResultsThe m6A methyltransferase METTL3 was upregulated during cancer cell ferroptosis and facilitated erastin-induced ferroptosis by enhancing mitochondrial ROS. Mechanistic studies showed that METTL3 negatively regulated the transcription and promoter activity of SLC7A11. Specifically, METTL3 induced H3K27 trimethylation of the SLC7A11 promoter by suppressing the mRNA stability of H3K27 demethylases KDM6B. Furthermore, METTL3 suppressed the expression of GATA3, which regulated SLC7A11 transcription by binding to the putative site at − 597 to − 590 of the SLC7A11 promoter. METTL3 decreased the precursor mRNA stability of GATA3 through m6A/YTHDF2-dependent recruitment of the 3′-5′ exoribonuclease Dis3L2. Targeted demethylation of KDM6B and GATA3 m6A using the dm6ACRISPR system significantly increased the expression of SLC7A11. Moreover, the transcription factor YY1 was responsible for erastin-induced upregulation of METTL3 by binding to its promoter-proximal site. In vivo and clinical data supported the positive roles of the METTL3/SLC7A11 axis in tumor growth and progression.ConclusionsMETTL3 regulated the transcription of SLC7A11 through GATA3 and KDM6B to modulate ferroptosis in an m6A-dependent manner. This study provides a novel potential strategy and experimental support for the future treatment of cancer.

The microenvironment cell index is a novel indicator for the prognosis and therapeutic regimen selection of cancers

BackgroundIt is worthwhile to establish a prognostic prediction model based on microenvironment cells (MCs) infiltration and explore new treatment strategies for triple-negative breast cancer (TNBC).MethodsThe xCell algorithm was used to quantify the cellular components of the TNBC microenvironment based on bulk RNA sequencing (bulk RNA-seq) data. The MCs index (MCI) was constructed using the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. Single-cell RNA sequencing (scRNA-seq), spatially resolved transcriptomics (SRT), and multiplex immunofluorescence (mIF) staining analyses verified MCI. The mechanism of action of the MCI was investigated in tumor-bearing mice.ResultsMCI consists of the six types of MCs, which can precisely predict the prognosis of the TNBC patients. scRNA-seq, SRT, and mIF analyses verified the existence and proportions of these cells. Furthermore, combined with the spatial distribution characteristics of the six types of MCs, an MCI-enhanced (MCI-e) model was constructed, which could predict the prognosis of the TNBC patients more accurately. More importantly, inhibition of the insulin signaling pathway activated in the cancer cells of the MCIhigh the TNBC patients significantly prolonged the survival time of tumor-bearing mice.ConclusionsOverall, our results demonstrate that MCs infiltration can be exploited as a novel indicator for the prognosis and therapeutic regimen selection of the TNBC patients.

Oral microbiota: the overlooked catalyst in cancer initiation and progression

The advancement of high-throughput sequencing technology in recent decades has led to a greater understanding of the components of the oral microbiota, providing a solid foundation for extensive research in this field. The oral microbiota plays an important role in an individual’s overall health. It has been shown to be significantly correlated with chronic human diseases, including diabetes, rheumatoid arthritis, cardiovascular disease, periodontal disease, and Alzheimer’s disease. Furthermore, tumor occurrence and development are closely related to the oral microbiome. Specific bacteria, such as Fusobacterium nucleatum (F. nucleatum), Porphyromonas gingivalis (P. gingivalis), Streptococcus, Streptomyces, Prevotella, and Fibrophagy gingivalis, play critical roles in cancer development. The oral microbiota has various oncogenic mechanisms, including bacterial inflammation, immunological suppression, tumor growth mediated by bacterial toxins, antiapoptotic activity, and carcinogenic effects. This paper reviews the role of the oral microbiota in the occurrence and progression of cancer and systematically elucidates the molecular mechanisms by which dysbiosis influences tumorigenesis and tumor progression. This information can provide a theoretical basis for exploring cancer treatment strategies and offer new insights for cancer prevention.

Efficient and Rapid Microfluidics Production of Bio-Inspired Nanoparticles Derived from Bombyx mori Silkworm for Enhanced Breast Cancer Treatment

Background/Objectives: In the quest for sustainable and biocompatible materials, silk fibroin (SF), derived from natural silk, has emerged as a promising candidate for nanoparticle production. This study aimed to fabricate silk fibroin particles (SFPs) using a novel swirl mixer previously presented by our group, evaluating their characteristics and suitability for drug delivery applications, including magnetic nanoparticles and dual-drug encapsulation with curcumin (CUR) and 5-fluorouracil (5-FU). Methods: SFPs were fabricated via microfluidics-assisted desolvation using a swirl mixer, ensuring precise mixing kinetics. Comprehensive physicochemical characterisation, including size, polydispersity index (PDI), zeta potential, and secondary structure analysis, was conducted. Further, CUR/5-FU-loaded magnetic core SFPs were assessed for cytotoxicity in vitro using breast cancer cell lines and for biodistribution and targeting efficiency in a murine breast cancer model. Results: The swirl mixer produced SFPs with sizes below 200 nm and uniform distributions (PDI < 0.20) with size stability for up to 30 days. Encapsulation efficiencies were 37% for CUR and 82% for 5-FU, with sustained drug release profiles showing 50% of CUR and 70% of 5-FU released over 72 h. In vitro studies demonstrated sustained cytotoxic effects, and cell cycle arrest at the G2/M phase in breast cancer cell lines, with minimal toxicity in non-cancerous cells. Cellular uptake assays confirmed efficient drug delivery to the cytoplasm. In vivo biodistribution studies revealed increased tumour-specific drug accumulation with magnetic guidance. Haematoxylin & Eosin (H&E) staining indicated enhanced tumour necrosis in treated groups compared to controls. Conclusions: This study underscores the utility of the swirl mixer for efficient and scalable fabrication of bio-inspired SFPs, supporting their application in targeted cancer drug delivery. These findings align with and advance previous insights into the use of microfluidics and desolvation methods, paving the way for improved therapeutic strategies in breast cancer treatment.

Development of Treatment Strategies for Advanced HER2-positive Gastric Cancer: Insights from Clinical Trials.

HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.

Treatment strategy for intermediate-risk papillary thyroid cancer: Focus on postoperative hypothyroidism following lobectomy.

An optimal surgical approach for intermediate-risk papillary thyroid cancer (PTC) has not yet been established. The surgical procedure should be determined based on treatment outcomes and postoperative complications. This study aimed to evaluate appropriate surgical strategies for patients with intermediate-risk PTC by comparing treatment outcomes and postoperative complications following total thyroidectomy and lobectomy. This retrospective analysis was conducted on 123 patients with intermediate-risk PTC treated in our department between January 2008 and December 2022. The risk of PTC was classified according to the 2024 Guidelines for the Clinical Treatment of Thyroid Nodules from the Japan Association of Endocrine Surgery. Of the 123 patients, 27 underwent total thyroidectomy, and 96 underwent lobectomy. No significant differences were observed between the two surgical groups in terms of survival or recurrence rates. None of the patients showed bilateral recurrent laryngeal nerve (RLN) palsy postoperatively. Postoperative unilateral RLN palsy occurrence differed significantly between the total thyroidectomy and lobectomy groups, with five cases in each (5.2 and 18.5 %, respectively; p = 0.04). Permanent hypoparathyroidism was observed in two patients (7.4 %) in the total thyroidectomy group. Postoperative hypothyroidism developed in 42 (43.8 %) lobectomy cases, with 32 requiring the administration of levothyroxine therapy. A significant association was observed between preoperative thyroid-stimulating hormone (TSH) levels (≥2.0 μIU/mL) and postoperative hypothyroidism (p < 0.001). No significant difference in treatment outcomes was observed between patients with intermediate-risk PTC who underwent total thyroidectomy and those who underwent lobectomy. In cases with preoperative TSH levels ≥2.0 μIU/mL, total thyroidectomy may be a more suitable approach, given the increased likelihood of requiring postoperative levothyroxine administration following lobectomy.

Royal Jelly's Strong Selective Cytotoxicity Against Lung Malignant Cells and Macromolecular Alterations in Cells Observed by FTIR Spectroscopy.

Several nutraceuticals, food, and cosmetic products can be developed using royal jelly. It is known for its potential health benefits, including its ability to boost the immune system and reduce inflammation. It is rich in vitamins, minerals, and antioxidants, which can improve general health. Royal jelly (RJ) is also being studied as a potential therapeutic agent for cancer and other chronic diseases. It is effective in reducing tumor growth and stimulating immunity. In this study, we investigated the effects of royal jelly on cancerous A549 cells and healthy MRC-5 cells at various doses ranging from 1.25 to 10 mg/ml. Royal jelly's anti-proliferative effect was evaluated by MTT and SRB assay for 48 h. The induction of necrosis and apoptosis was assessed by flow cytometry as well. The relative amounts of major molecules in Royal jelly were determined by FTIR spectroscopy to identify key functional groups and molecular structures. In addition, this technique was used for the first time to detect changes in the macromolecular composition of lung cells treated with royal jelly. Thus, it provided insights into the relative abundance of proteins, lipids, and carbohydrates, which could correlate with their bioactive properties. The antiproliferative effect of Royal jelly was found to be selective on A549 cells in a dose-dependent manner with an IC50 of 9.26 mg/mL, with no cytotoxic effects on normal MRC-5 cells. Moreover, Royal jelly induced predominantly necrotic cell death in A549 cells, %39.10 at 4 mg/ml and %57.88 at 10 mg/ml concentrations. However, the necrosis rate in MRC-5 cells was quite low, at 9.16% and 20.44% at the same doses. Royal jelly showed dose-dependent selective cytotoxicity toward A549 cells, whereas it exhibited no apparent cytotoxicity in MRC-5 cells. In order to identify the biomolecular changes induced by royal jelly, we used two unsupervised chemometric pattern recognition algorithms (PCA and HCA) on the preprocessed sample FTIR spectra to determine the effects of royal jelly on cell biochemistry. According to PCA and HCA results, RJ treatments especially affected biomolecules in A549 cells. The total spectral band variances in the PCA loading spectra were calculated for understanding biomolecular alterations. These plots revealed profound changes in the lipid, protein, and nucleic acid content of RJ-applied lung cells, primarily identifying RJ and H2O2 treated groups for A549 cells. Ultimately, the selective cytotoxicity of royal jelly toward A549 cancerous cells suggests that royal jelly may be a promising therapeutic agent for identifying innovative lung cancer treatment strategies. Additionally, understanding the molecular alterations induced by royal jelly could guide the development of novel cancer treatments that exploit its bioactive properties. This could lead to more effective and safer therapies.

Triple-action cancer therapy using laser-activated NO-releasing metallomicellar nanophotosensitizer for pyroptosis-driven immune reprogramming.

Cancer photoimmunotherapy represents an intelligent and highly efficient therapeutic approach that harnesses the photothermal effect to precisely target and ablate tumor tissues, while simultaneously modulating the immune system to achieve tumor elimination. The integration of multifunctional therapeutic modalities for combined photoimmunotherapy requires advanced drug delivery systems. However, the design of a single nanoagent capable of serving as a multifunctional nanophotosensitizer remains a significant challenge. In this study, we developed a metallomicellar nanophotosensitizer named TAGNO, which offers a synergistic tri-modal cancer treatment strategy by combining photothermal therapy (PTT), gas therapy (GT), and immunotherapy. The TAGNO nanophotosensitizer consists of a gold nanorod core, responsible for inducing the photothermal effect, coated with an amphiphilic polymer functionalized with tumor cell penetrating peptide to accommodate lipophilic small molecule BNN6, a nitric oxide (NO) donor for GT. We demonstrated that TAGNO exhibited high tumor accumulation, excellent stability, and biocompatibility, ensuring the safe delivery of NO to the tumor site. Upon near-infrared (NIR) laser irradiation, TAGNO effectively raised the temperature within tumor tissues while sparing the surrounding healthy tissues and enabled controlled NO release. Once released, the NO interacts with hydrogen peroxide in the hypoxic tumor microenvironment, forming peroxynitrite (ONOO-), which induces mitochondrial dysfunction and triggers pyroptotic cell death. Pyroptosis induced immunogenic cell death and the subsequent release of tumor antigens, activating cytotoxic T cells and promoting M1 macrophage polarization, effectively controlling both primary and secondary tumor growth. Furthermore, laser-induced NO release facilitated the relaxation of stiff tumor tissues, enhancing blood vessel dilation and oxygenation. This improvement promoted immune cell infiltration while suppressing immunosuppressive cells. Overall, this innovative combination of PTT, GT, and immunotherapy presents a potent and synergistic strategy for the treatment of malignant colon tumors, achieving complete tumor eradication.

Cabozantinib Selectively Induces Proteasomal Degradation of p53 Somatic Mutant Y220C and Impedes Tumor Growth.

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multi-kinase inhibitor currently used in clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting in the dissociation of p53Y220C protein from its binding with USP7 and subsequent ubiquitination and degradation mediated by CHIP (The carboxyl terminal of Hsp70-interacting protein). We also show that cabozantinib displays preferential cytotoxicity to p53Y220C-harboring cancer cells both in vitro and in vivo. This study demonstrates a novel, p53-Y220C mutant-targeted anticancer action and mechanism for cabozantinib, and provides the rationale for use of this drug in treatment of cancers that carry the p53-Y220C mutation.

Albumin-based nanocarriers loaded with novel Zn(II)-thiosemicarbazone compounds chart a new path for precision breast cancer therapy.

This study explores the therapeutic potential of albumin-bound Zn(II)-thiosemicarbazone compounds (Alb-ZnTcA, Alb-ZnTcB) against breast cancer cells. Previous research indicates that these compounds hinder cancer cell proliferation by blocking DNA synthesis, promoting oxidative stress to induce apoptosis, and disrupting the cell cycle to inhibit cellular division. This study focuses on the loading and characterization of these potentially chemically unstable compounds on bovine serum albumin-based nanocarriers. Accordingly, unlike previous studies using albumin nanoparticles, in this study, ultraviolet light was used to precisely bind the therapeutic agent to albumin during the integration of thiosemicarbazones, achieving controlled nanoparticle size to control nanoparticle size. The mean diameter of Alb-ZnTcA nanoparticles was 32 nm, while Alb-ZnTcB exhibited an average diameter of 43 nm. Notably, Alb-ZnTcA displayed the highest cytotoxicity toward breast cancer cells, suggesting an optimal size for cellular uptake. Additionally, albumin-bound compounds showed enhanced cytotoxicity at lower concentrations, potentially minimizing adverse side effects. Apoptosis analysis indicated that both Alb-ZnTcA and Alb-ZnTcB induce cell death predominantly through apoptosis, effectively preventing the uncontrolled proliferation of cancer cells. These findings demonstrate the potential of Zn(II)-thiosemicarbazone compounds loaded on albumin-based nanocarriers for breast cancer treatment. The increased potency of Alb-ZnTcA and Alb-ZnTcB compared to free compounds, along with their ability to activate apoptotic signaling pathways in MCF-7 breast cancer cells, highlights a promising approach for future cancer therapies. This study suggests that albumin-bound Zn(II)-thiosemicarbazone compounds could offer a targeted and effective strategy in breast cancer treatment, leveraging the advantages of nanocarrier-based delivery systems.

Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors.

The genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies. Here, we perform integrative analysis of genome-wide loss of heterozygosity and expression to identify potential tumor suppressor genes. The functions and mechanisms of one of the candidates, TACC2, are then explored both invitro and invivo, leading to the proposal of a therapeutic strategy based on the concept of synthetic lethality. We reveal that the inactivation of TACC2, due to copy number loss and promoter hypermethylation, is associated with poor prognosis in ESCC patients. TACC2 depletion enhances ESCC tumorigenesis and progression, as demonstrated in Tacc2 knockout mouse models and by increased growth abilities of ESCC cells. Mechanistically, TACC2 interacts with components of the NuRD and CoREST co-repressor complexes, including MTA1, MBD3, and HMG20B, in the cytoplasm. TACC2 loss leads to the translocation of these proteins into the nucleus, facilitating the formation of functional NuRD and CoREST complexes and the epigenetic repression of CDKN1A. This repression results in elevated CDK1/2 activation. Furthermore, TACC2-deficient cells and ESCC patient-derived organoids with reduced TACC2 expression show increased sensitivity to CDK inhibitors, particularly dinaciclib, which is currently in a phase III trial. Notably, the combination of TACC2-specific RNAi and dinaciclib in subcutaneous ESCC models significantly impairs tumor growth. The findings suggest a strategy for cancer treatment based on synthetic lethality. Funded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP.

DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting.

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein of interest (POI) ligand and an E3 ligase ligand connected by a linker, which can recruit POI and E3 ligases simultaneously, thereby inducing the degradation of POI and showing great potential in disease treatment. A challenge in developing PROTACs is the design of linkers and the modification of ligands to establish a multifunctional platform that enhances degradation efficiency and antitumor activity. As a programmable and modifiable nanomaterial, DNA tetrahedron can precisely assemble and selectively recognize molecules and flexibly adjust the distance between molecules, making them ideal linkers. Herein, we developed a multivalent PROTAC based on a DNA tetrahedron, named AS-TD2-PRO. Using DNA tetrahedron as a linker, we combined modules targeting tumor cells, recognizing E3 ligases, and multiple POI together. We took the undruggable target protein signal transducer and activator of transcription 3 (STAT3), associated with the etiology and progression in a variety of malignant tumors, as an example in this study. AS-TD2-PRO with two STAT3 recognition modules demonstrated good potential in enhancing tumor-specific targeting and degradation efficiency compared to traditional bivalent PROTACs. Furthermore, in a mouse tumor model, the superior therapeutic activity of AS-TD2-PRO was observed. Overall, DNA tetrahedron-driven multivalent PROTACs both serve as a proof of principle for multifunctional PROTAC design and introduce a promising avenue for cancer treatment strategies.

Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Reactive oxygen species and its manipulation strategies in cancer treatment.

Cancer is one of the serious diseases of modern times, occurring in all parts of the world and shows a wide range of effects on the human body. Reactive Oxygen Species (ROS) such as oxide and superoxide ions have both advantages and disadvantages during the progression of cancer, dependent on their concentration. It is a necessary part of the normal cellular mechanisms. Changes in its normal level can cause oncogenesis and other relatable problems. Metastasis can also be controlled by ROS levels in the tumor cells, which can be prevented by the use of antioxidants. However, ROS is also used for the initiation of apoptosis in cells by different mediators. There exists a cycle between the production of oxygen reactive species, their effect on the genes, role of mitochondria and the progression of tumors. ROS levels cause DNA damage by the oxidation process, gene damage, altered expression of the genes and signalling mechanisms. They finally lead to mitochondrial disability and mutations, resulting in cancer. This review summarizes the important role and activity of ROS in developing different types of cancers like cervical, gastric, bladder, liver, colorectal and ovarian cancers.

An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.

This review provides a comprehensive overview of the recent advancements in research on ATF4 (Activating Transcription Factor 4) within the field of oncology. As a crucial transcription factor, ATF4 has garnered increasing attention for its role in cancer research. The review begins with an exploration of the regulatory mechanisms of ATF4, including its transcriptional control, post-translational modifications, and interactions with other transcription factors. It then highlights key research findings on ATF4's involvement in various aspects of tumor biology, such as cell proliferation, differentiation, apoptosis and survival, invasion and metastasis, and the tumor microenvironment. Furthermore, the review discusses the potential of targeting ATF4 as a novel therapeutic strategy for cancer treatment. It also explores how ATF4's interactions with existing anticancer drugs could inform the development of more effective therapeutic agents. By elucidating the role of ATF4 in tumor biology and its potential clinical applications, this review aims to provide new insights and strategies for cancer treatment.