Tumor Research Articles

Facile Synthesis of Fe‐Based Metal‐Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis

AbstractMild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat‐induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo‐tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe‐based metal‐quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers

Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

An Aged Tree with a New Bloom: A Simple Spatiotemporal Programming Strategy Enables Carbon Dot Photosensitizers to Regulate Cell Pyroptosis for Enhanced Tumor Photodynamic-Immunotherapy.

Pyroptosis induced by photodynamic therapy (PDT) is a promising field in both PDT and immunotherapy for tumors. However, effectively inducing tumor cell pyroptosis while triggering a strong immune response using current photosensitizers remains challenging. Herein, the developed positively charged carbon dots (PCDs) nanoPSs were utilized to modulate tumor cell pyroptosis for the first time through a simple spatiotemporal programming strategy. Briefly, PCDs enabled precisely time-dependent targeting of the cell membrane or lysosome. Upon light irradiation, in vitro studies revealed that lysosome-targeted PDT primarily induced apoptosis, while membrane-targeted PDT triggered pyroptosis, resulting in enhanced PDT efficacy and robust activation of the immune response. Conclusively, in vivo studies demonstrated that PCDs could serve as a novel pyroptosis nanotuner for enhanced photodynamic-immunotherapy, thereby simultaneously eliminating primary tumors and inhibiting distant tumor growth and metastases. This spatiotemporal programming strategy unprecedentedly offers a rejuvenation of aged PSs and expands the biomedical use of CDs in immunotherapy.

Cascade-catalysed nanocarrier degradation for regulating metabolism homeostasis and enhancing drug penetration on breast cancer.

The abnormal structure of tumor vascular seriously hinders the delivery and deep penetration of drug in tumor therapy. Herein, an integrated and tumor microenvironment (TME)-responsive nanocarrier is designed, which can dilate vessle and improve the drug penetration by in situ releasing nitric oxide (NO). Briefly, S-nitroso-glutathione (GSNO) and curcumin (Cur) were encapsulatd into the Cu-doped zeolite imidazole framework-8 (Cu-ZIF-8) and modified with hyaluronic acid. The nanocarrier degradation in the weakly acidic of TME releases Cu2+, then deplete overexpressed intratumourally glutathione and transformed into Cu+, thus disrupting the balance between nicotinamide adenine dinucleotide phosphate and flavin adenine dinucleotide (NADPH/FAD) during the metabolism homeostasis of tumor. The Cu+ can generate highly toxic hydroxyl radical through the Fenton-like reaction, enhancing the chemodynamic therapeutic effect. In addition, Cu+ also decomposes GSNO to release NO by ionic reduction, leading to vasodilation and increased vascular permeability, significantly promoting the deep penetration of Cur in tumor. Afterwards, the orderly operation of cell cycle is disrupted and arrested in the S-phase to induce tumor cell apoptosis. Deep-hypothermia potentiated 2D/3D fluorescence imaging demonstrated nanocarrier regulated endogenous metabolism homeostasis of tumor. The cascade-catalysed multifunctional nanocarrier provides an approach to treat orthotopic tumor.

Preparation of DOX-TPP/HA-ss-OA Nanoparticles, Investigation of Drug Release Behavior In Vitro, and Evaluation of Anti-proliferative Activity In Vitro.

This study aimed to develop and characterize DOX-TPP/HA-ss-OA nanoparticles, utilizing the mitochondria-targeting prodrug doxorubicin-triphenylphosphine (DOXTPP) and a reduction-sensitive amphiphilic polymer, hyaluronic acid-disulfide-oleic acid (HAss- OA). The research focused on evaluating the drug release behavior of these nanoparticles under varying glutathione (GSH) concentrations and their anti-tumor activity in vitro. DOX-TPP/HA-ss-OA nanoparticles were prepared using probe ultrasound technology. The study examined the impact of different organic solvents on drug loading capacity and encapsulation efficiency to determine the optimal conditions. A single-factor experimental design was used to optimize the formulation process. Key parameters, including particle size and zeta potential, were measured to assess nanoparticle stability and performance. The dynamic dialysis method was employed to evaluate the reduction-sensitive drug release characteristics in media with different GSH concentrations. The MTT assay was used to analyze the growth-inhibitory effects of the nanoparticles on human breast cancer cells (MCF-7) and drug-resistant cells (MCF-7/ADR). The optimized preparation process for DOX-TPP/HA-ss-OA nanoparticles included a drug dosage of 2.0 mg, an oil-to-water volume ratio of 1:5, ultrasonic power of 500 W, and ultrasonic time of 15 minutes. The nanoparticles had an average particle size of 203.72 ± 2.30 nm and a zeta potential of 25.82 ± 0.58 mV, indicating favorable stability and effective drug delivery properties. The nanoparticles exhibited a slow, sustained release of DOX-TPP in pH 7.4 phosphate buffer solution (PBS) and accelerated release in high GSH concentrations, demonstrating reduction-responsive drug release. In vitro studies showed that DOX-TPP/HA-ss-OA nanoparticles significantly inhibited the proliferation of MCF-7 and MCF-7/ADR cells in a dosedependent manner, with enhanced efficacy compared to free DOX and other formulations. DOX-TPP/HA-ss-OA nanoparticles demonstrate excellent reduction sensitivity, effective tumor cell growth inhibition in vitro, and the ability to overcome drug resistance. Including particle size and zeta potential measurements supports their suitability as drug carriers, highlighting their potential for targeted cancer therapy and further development.

Multi-Omic Characterization of Single Cells and Cell-Free Components Detected in the Cerebrospinal Fluid of Patients with Leptomeningeal Disease

Background/Objectives: Up to 30% of patients with breast cancers will develop brain or leptomeningeal metastases, and this risk is especially high with HER2-positive cancers. For patients with central nervous system metastases, cerebrospinal fluid (CSF) liquid biopsies are a promising opportunity to monitor disease, inform treatment, and predict prognosis. This pilot study investigated CSF liquid biopsy analytes from three patients diagnosed with central nervous system metastases based on imaging but not confirmed via clinical cytology. Methods: The detection of cellular analytes with the non-enrichment high-definition single-cell assay (HDSCA3.0) workflow was compared between the CSF and matched peripheral blood (PB) samples. Results: Circulating tumor cells (CTCs) were detected in the CSF but not the PB and were subsequently molecularly characterized using single-cell genomics and targeted multiplexed proteomics to reveal a clonal population of phenotypically heterogeneous cells. There was a lack of concordance in the copy number alteration profiles between CTCs and cell-free DNA (cfDNA) in the CSF. Extracellular vesicle surface marker analysis in CSF revealed a prominent signal among tetraspanins (CD9/CD63/CD81), with CD81 exhibiting the highest signal across all patients. Conclusions: The data presented suggest that CSF could be a useful tool for diagnosing and assessing disease severity.

Neoantigen prioritization based on antigen processing and presentation

Somatic mutations in tumor cells give rise to mutant proteins, fragments of which are often presented by MHC and serve as neoantigens. Neoantigens are tumor-specific and not expressed in healthy tissues, making them attractive targets for T-cell-based cancer immunotherapy. On the other hand, since most somatic mutations differ from patient to patient, neoantigen-targeted immunotherapy is personalized medicine and requires their identification in each patient. Computational algorithms and machine learning methods have been developed to prioritize neoantigen candidates. In fact, since the number of clinically relevant neoantigens present in a patient is generally limited, this process is like finding a needle in a haystack. Nevertheless, MHC presentation of neoantigens is not random but follows certain rules, and the efficiency of neoantigen detection may be further improved with technological innovations. In this review, we discuss current approaches to the detection of clinically relevant neoantigens, with a focus on antigen processing and presentation.

A novel ITGB8 transcript variant sustains ovarian cancer cell survival through genomic instability and altered ploidy on a mutant p53 background.

Transcript variants and protein isoforms are central to unique tissue functions and maintenance of homeostasis, in addition to being associated with aberrant states such as cancer, where their crosstalk with the mutated tumor suppressor p53 may contribute to genomic instability and chromosomal rearrangements. We previously identified several novel splice variants in ovarian cancer RNA-sequencing datasets; herein, we aimed to elucidate the biological effects of the Integrin Subunit Beta 8 variant (termed pITGB8-205). Resolution of the full-length sequence of pITGB8-205 through rapid amplification of cDNA ends (RACE-PCR). Cell cycle analysis and karyotype studies were performed to further explore genomic instability. RNA-seq and proteomics analyses were used to identify the differential expression of the genes. This full-length study revealed a unique 5' sequence in pITGB8-205 that differed from the reported ITGB8-205 sequence, suggesting differential regulation of this novel transcript. Under a p53 mutant background, overexpression of pITGB8-205 triggered genetic instability reminiscent of oncogene-induced replicative stress with extensive abnormal mitoses and chromosomal and nuclear aberrations indicative of chromosomal instability, leading to near whole-genome duplication that imposes energy stress on cellular resources. Micronuclei and aneuploidy are striking features of pITGB8-205-overexpressing p53-mutant cells but are not enhanced in p53 wild-type (WT) cells. RNA-seq and proteomics analyses further suggested that p53 inactivation in ovarian cancer provides a permissive intracellular molecular niche for pITGB8-205 to mediate its effects on genomic instability. This observation is pivotal considering that most high-grade serous ovarian carcinoma (HGSC) tumors express mutant p53. The resulting aneuploid clones with enhanced self-renewal and survival capabilities disrupt clonal dominance under stress yet maintain a balance between replicative stress and prosurvival advantages. pITGB8-205-overexpressing clones sustain ovarian tumor cell survival, achieve homeostasis and are formidable opponents of therapy.

Expression of p53 Protein in Different Grades of Gastric Carcinoma

Background: Mutation in the TP53 suppressor gene and accumulation of p53 protein are the common genetic events in gastric carcinomas. This mutation has been associated with abnormalities in cell cycle regulation, DNA repair and synthesis, apoptosis, and suggested to be implicated in the prognosis of gastric carcinoma. Objectives: To assess the immunohistochemical expression of p53 protein in gastric carcinoma and to study the association of p53 protein expression with different histopathological grade of gastric carcinoma. Methods: In this cross-sectional observational study, 60 paraffin blocks of gastric adenocarcinoma were re-evaluated and histopathological grading were assessed. The p53 expression in the tumour cell nucleus of the submitted blocks were assessed by standard immunoperoxidase method. Appropriate positive control was run for each batch of slides. Results: Out of 60 cases, most of them 35 cases were poorly differentiated carcinoma, of which 28(80%) showed high expression and 7(20%) showed low expression of p53 protein. Twenty cases were moderately differentiated carcinoma, of which 12(60%) showed high expression and 8(40%) low expression. Only 5 were well differentiated carcinoma and all of which showed low expression of p53 protein. So, it was seen that with advancing grade of tumor, frequency of high expression of p53 protein was high and yielded statistically significant result (p value = 0.001). Conclusion: There was a significant association between immunohistochemical expression of p53 protein and histopathological grading of gastric adenocarcinoma. These results indicate that immunohistochemical expression of p53 protein is an important prognostic factor of gastric adenocarcinoma, allowing the selection of a group of patients with an extensive therapeutic indication. Mediscope 2024;11(2): 48-51

Is Serum Ferritin a Predictor of Blood Transfusions Outcome and Survival in Childhood Lymphomas and Solid Tumors?

Packed red blood cell (PRBC) transfusions are an important part of supportive treatment in oncology; however, when used frequently, they can be a result of transfusion-related iron overload. The aim of the study was to evaluate the role of ferritin as a non-specific marker of neoplastic growth and transfusion-related iron overload in children with lymphomas and solid tumors. We performed a longitudinal analysis of PRBC transfusions and changes in ferritin concentrations during oncological treatment of 88 children with lymphomas and solid tumors. A ferritin concentration above 500 ng/mL was diagnosed in 14.77% of patients at the moment of admission and 18.18% at the end of treatment. No differences were shown in serum ferritin in the context of tumor type-, sex-, and transfusion-related parameters. Those above the age of 10 demonstrated higher ferritin concentrations compared to subjects younger than 5 years of age. In addition, those over than 10 years old or above 30 kg in weight showed a tendency for better survival. All tested patients demonstrated highly significant correlations between ferritin at the 15th month of treatment or after therapy discontinuation and transfusion-related parameters. Interestingly, ferritin levels were found to lower back to the values before therapy shortly after its discontinuation. Transfusion parameters and ferritin levels had no influence on the survival of the studied cancer patients.

Demonstration of T-Cell Monotypia Using Anti-TCRbeta1/2 (TRBC1/2) Immunostaining as a Rapid and Cost-Effective Alternative to PCR-Based Clonality Studies for the Diagnosis of T-Cell Lymphoma

Background/Objectives: T-cell lymphomas are often histologically indistinguishable from benign T-cell infiltrates, and diagnosis typically relies on slow, complex, and expensive multiplexed PCR reactions, requiring significant training and experience to interpret them. We aimed to raise highly specific antibodies against the two alternatively used and very similar T-cell receptor beta constant regions, TCRbeta1 and TCRbeta2, encoded by the TRBC1 and TRBC2 gene segments, respectively. We sought to demonstrate the feasibility of detecting TCRbeta1 and TCRbeta2 immunohistochemically in routine clinical (formalin-fixed, paraffin-embedded (FFPE)) tissue sections as a novel diagnostic strategy for T-cell lymphomas. Methods: Recombinant rabbit antibodies were validated using Western blotting and FFPE immunostaining of T-cell leukemia lines. The immunostaining of FFPE tissue containing benign and lymphomatous T-cell populations was undertaken, with corroboration by BaseScopeTM high-sensitivity in situ hybridization and quantitative real-time PCR (Q-PCR). An additional Q-PCR literature review and analysis of publicly available RNAseq data was used to determine the TCRbeta2/TCRbeta1 ratio cut-off to separate benign and malignant T-cell populations. Results: Our TCRbeta1/TCRbeta2 antibody pair gave highly specific FFPE tissue staining. All benign samples analyzed (immunohistochemically, by BaseScopeTM, by Q-PCR, and by RNAseq data analysis) had TCRbeta1/TCRbeta2 or TRBC1/TRBC2 ranges well within the previously published flow cytometric benign range (TCRbeta2/TCRbeta1 = 0.18:1–5.7:1), while samples of T-cell lymphoma did not. One out of thirteen (7.7%) lymphoma samples showed some detectable TCRbeta1/TCRbeta2 protein co-expression, and 4 out of 13 (30.8%) T-cell lymphomas showed a TRBC1/TRBC2 transcript co-expression using BaseScopeTM. Conclusions: Analyzing T-cell monotypia immunohistochemically, analogous to B-cell monotypia (kappa: lambda ratio for B-cell and plasma cell neoplasms), could make the diagnosis of T-cell lymphomas cheaper, quicker, and more accurate. Larger studies are needed to validate our antibodies for clinical use.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Construction of Somatostatin-Based Multiphase "Core-Shell" Coacervates as Photodynamic Biomimetic Organelles.

Biomimetic coacervates have recently attracted great interest in biomedical fields, especially for drug delivery and as protocells. However, these membraneless structures are easily coalesced and poorly targetable, limiting their real biomedical applications. Here multiphase "core-shell" coacervate (CSC) constructed by dsDNA and somatostatin (SST), a 14-mer cyclopeptide is designed. The CSC shows enhanced tumor targetability through SST binding to SST receptors on the tumor cells' surface. G4 quadruplex-hemin complex can be embedded in the CSC by interaction with SST, as demonstrated by molecular simulation and isothermal titration calorimetry. The G4-hemin embedded CSC can further recruit photosensitizers such as tetracarboxyphenyl porphyrin to form the CSC-GHT composite for photodynamic therapy (PDT). As photodynamic biomimetic organelles, CSC-GHT can convert oxygen to singlet oxygen (catalyzed by the catalase-mimetic activity of G4-hemin), resulting in enhanced PDT effect, which allows the inhibition of cellular migration in vitro and tumor growth in vivo. Owing to high stability, targetability, and biosafety, the proposed CSC can recruit various cargos from small dyes to large biomacromolecules (up to 430kDa), providing promising theranostic applications.

Patient-Derived Organoids on a Microarray for Drug Resistance Study in Breast Cancer.

Drug resistance is always a challenge in cancer treatment, whether for chemotherapy, targeting, or immunotherapy. Although tumor cell lines are derived from cancer patients, they gradually lost the original characteristics, including heterogeneity and tumor microenvironment (TME), during the long period of in vitro culturing. Therefore, it is urgent to use patient-derived tumor models instead of cancer cell lines to study tumor drug resistance. Herein, we developed a microarray device that serves as a platform for high-throughput and three-dimensional culture of breast cancer patient-derived organoids (BCOs) and investigated their resistance to adriamycin (ADM). Coupled with fluorescence microscopy, this system enabled on-chip drug response monitoring and cell viability assessment without the consumption of a large number of tumor cells. The organoids were divided into a resistant BCO group (RBCO) and a sensitive BCO group (SBCO) according to their half-inhibitory concentration (IC50). Different from cancer cell lines, BCOs demonstrated obvious heterogeneity in drug treatment. Ivermectin (IVM), a broad-spectrum antiparasitic agent approved by the Food and Drug Administration (FDA), was observed to synergistically augment ADM-induced cytotoxicity in organoids. The BCO chip provides a promising platform for investigation of drug resistance and preclinical drug screening based on clinical samples.

Ultrasound‐Responsive Lipid Nanoparticles for Targeted Therapy and Controlled Drug Release in Non‐Small Cell Lung Cancer

AbstractMultifunctional drug delivery systems offer tremendous potential for improving antitumor efficacy, precise drug targeting, and controlled drug release in treating non‐small cell lung cancer (NSCLC). In this study, the study develops a novel tumor‐targeting ultrasound‐responsive lipid nanoparticle (TUSL) platform capable of responding to external stimulation, enabling precise drug delivery with controlled release at the tumor site while minimizing systemic exposure and side effects. The TUSL platform is designed to carry doxorubicin (DOX) and tetrandrine (TET), specifically for drug‐resistant NSCLC. The developed TUSL exhibits a nano sized spherical structure with a hydrodynamic size of 141.8 nm, accommodating anti‐cancer drugs with loading capacities of 3.8% and 6.2% for TET and DOX, respectively. TUSL is engineered to target the epidermal growth factor receptor (EGFR) while demonstrating an ultrasound‐triggered drug release profile. Through the generation of CO2 bubbles upon ultrasound stimulation, the TUSL enhances DOX and TET internalization into tumor cells. In tumor‐bearing mice, TUSL administration demonstrates a superior tumor accumulation with minimal off‐target toxicity. The combined treatment with DOX and TET within TUSL exhibits synergistic effects, effectively inhibiting the growth of drug‐resistant NSCLC tumors. These findings highlight the efficacy of the EGFR‐targeted TUSL formulation in overcoming drug resistance and enhancing therapeutic outcomes in NSCLC.

Hypermethylation of CDKN2A CpG island drives resistance to PRC2 inhibitors in SWI/SNF loss-of-function tumors.

Polycomb repressive complex 2 (PRC2) catalyzes the writing of the tri-methylated histone H3 at Lys27 (H3K27me3) epigenetic marker and suppresses the expression of genes, including tumor suppressors. The function of the complex can be partially antagonized by the SWI/SNF chromatin-remodeling complex. Previous studies have suggested that PRC2 is important for the proliferation of tumors with SWI/SNF loss-of-function mutations. In the present study, we have developed an EED-directed allosteric inhibitor of PRC2 termed BR0063, which exhibits anti-proliferative properties in a subset of solid tumor cell lines harboring mutations of the SWI/SNF subunits, SMARCA4 or ARID1A. Tumor cells sensitive to BR0063 exhibited several distinct phenotypes, including cell senescence, which was mediated by the up-regulation of CDKN2A/p16. Further experiments revealed that the expression of p16 was suppressed in the BR0063-resistant cells via DNA hypermethylation in the CpG island (CGI) promoter region, rather than via PRC2 occupancy. The expression of TET1, which is required for DNA demethylation, was found to be inversely correlated with p16 CGI methylation, and this may serve as a biomarker for the prediction of resistance to PRC2 inhibitors in SWI/SNF LOF tumors.

Capturing Hydrophilic Chemotherapeutics Agents Into siRNA-Encapsulated Vesicle-Like Nanoparticles for Convenient ICB-Chemo Combination Therapy.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

Evaluation of the anticancer properties of the phytochemicals present in <em>Annona muricata</em>

Cancer is a complex disease characterized by the unrestrained proliferation and dissemination of abnormal cells. The issue continues to be a notable public health concern on a global scale, with millions of new cases and fatalities being reported annually. Despite significant advances in cancer treatment, it remains a major challenge due to the high cost and toxicity of current therapies. Phytochemicals naturally found in plants are crucial resources for developing novel drugs and potential cancer therapies. The clinical efficacy of these anti-cancer agents has been demonstrated against diverse neoplastic cell lines. Additional investigation in this field can result in improved cancer therapies. Among many other plants effective against cancer, this literature review explores the anti-cancer properties of Annona muricata, a plant commonly known as soursop, which is a tropical plant species native to Central and South America, the Caribbean, and West Africa known for its edible fruit which has some medicinal merits, but also some toxicological effects. Annona muricata has been traditionally used for medicinal purposes, including cancer treatment. Acetogenins, alkaloids, phenolic compounds, and other active compounds are only a few of the phytochemicals that this review cites as being present in A. muricata. The review also looks into A. muricata’s biological abilities to fight lung, liver, prostate, colon, pancreas, and breast cancers. The toxicity of A. muricata and possible adverse effects are also covered in the review. The review also looks at the usage of nanoparticles with A. muricata as a cancer treatment. Overall, this literature review provides valuable insights into the potential anti-cancer properties of A. muricata and its potential as a therapeutic agent in cancer treatment.

Cancer-Specific Integrin Imaging With 68Ga-Trivehexin: A Potential Imaging for Accurate Staging of Thyroid Malignancy.

68Ga-Trivehexin is a novel radiotracer binding to "cancer-specific integrin αvβ6." 68Ga-Trivehexin has high specificity for tumor cells and, thus, has the potential to replace 18F-FDG PET/CT due to its limited specificity in the head and neck cancer. Here, we present one case of papillary thyroid carcinoma, where 68Ga-Trivehexin PET CT demonstrated accurate staging compared with 18F-FDG PET/CT.