Strategy For Treatment Of Tumors Research Articles

Targeting APE1: Advancements in the Diagnosis and Treatment of Tumors.

With the emergence of the precision medicine era, targeting specific proteins has emerged as a pivotal breakthrough in tumor diagnosis and treatment. Apurinic/apyrimidinic Endonuclease 1 (APE1) is a multifunctional protein that plays a crucial role in DNA repair and cellular redox regulation. This article comprehensively explores the fundamental mechanisms of APE1 as a multifunctional enzyme in biology, with particular emphasis on its potential significance in disease diagnosis and strategies for tumor treatment. Firstly, this article meticulously analyzes the intricate biological functions of APE1 at a molecular level, establishing a solid theoretical foundation for subsequent research endeavors. In terms of diagnostic applications, the presence of APE1 can be detected in patient serum samples, biopsy tissues, and through cellular in situ testing. The precise detection methods enable changes in APE1 levels to serve as reliable biomarkers for predicting tumor occurrence, progression, and patient prognosis. Moreover, this article focuses on elucidating the potential role of APE1 in tumor treatment by exploring various inhibitors, including nucleic acid-based inhibitors and small molecule drug inhibitors categories, and revealing their unique advantages in disrupting DNA repair function and modulating oxidative-reduction activity. Finally, the article provides an outlook on future research directions for APE1 while acknowledging major technical difficulties and clinical challenges that need to be overcome despite its immense potential as a target for tumor therapy.

Metal Doping Enabling Defective CoMo-Layered Double Hydroxide Nanosheets as Highly Efficient Photosensitizers for NIR-II Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) is attracting widespread attention as a promising strategy for tumor treatment. However, the efficacy of PDT is severely limited by the insufficient tissue penetration depth of the light source and low reactive oxygen species (ROS) generation efficiency. Herein, the metal doping strategy is reported to construct a series of defect-rich M-doped amorphous CoMo-layered double hydroxide (a-M-CoMo-LDH, M = Mn, Cu, Al, Ni, Mg, Zn) photosensitizers (PSs) for NIR-II PDT. Especially, M-doped CoMo-LDH nanosheets are synthesized through a simple hydrothermal method and then etched by acid treatment to prepare defect-rich a-M-CoMo-LDH nanosheets. Under NIR-II 1270 nm laser irradiation, the defect-rich a-Zn-CoMo-LDH nanosheets exhibit the optimal PDT performance compared with other a-M-CoMo-LDH nanosheets, and also possess much higher ROS production activity (3.9 times) than that of the pristine a-CoMo-LDH, with a singlet oxygen quantum yield up to 1.86, which is the highest among all the reported PSs. After polyethylene glycol (PEG) modification, the a-Zn-CoMo-LDH-PEG nanosheets can function as an effective inorganic PS for PDT, effectively inducing cell apoptosis in vitro and eradicating tumors in vivo. Notably, transcriptome sequencing analysis and further molecular validation highlight the critical role of the apoptotic/p53/AMPK/oxidative phosphorylation signaling pathways in a-Zn-CoMo-LDH-PEG-induced cancer cell apoptosis.

RVG29-modified oncolytic herpes simplex virus for intracranial tumor treatment

Oncolytic virus therapy for brain tumors has achieved breakthrough progress in clinical applications, yet its potential is severely constrained by the mode of administration-direct intratumoral injection into the cranial cavity. Other administration routes face rapid clearance by neutralizing antibodies and obstacles posed by the blood-brain barrier. Herein, we engineered the oncolytic herpes simplex virus type 2 (OH2) with surface modifications of polyethylene glycol (PEG) and rabies virus glycoprotein 29 (RVG29, a BBB-penetrating peptide from the rabies virus), to form OH2-PEG-RVG. OH2-PEG-RVG could efficiently traversed the blood-brain barrier even in BALB/c mice with pre-existing anti-OH2 antibodies, leading to the accumulation of OH2 in the brain. More importantly, OH2-PEG-RVG maintained blood-brain barrier integrity without causing pathological changes or behavioral abnormalities in mice. Furthermore, OH2-PEG-RVG effectively inhibited brain tumor growth, transforming immunologically "cold" tumors into "hot" tumors, inducing a robust anti-tumor immune response, and prolonging the survival of the mice. These findings underscore the potential of OH2-PEG-RVG as a multifaceted therapeutic strategy for effective brain tumor treatment, offering insights into addressing blood-brain barrier limitations.

TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas.

Pituitary adenomas (PAs) are common intracranial tumors and TRIM family plays a crucial role in cell proliferation, and therapeutic resistance of tumors. However, the role of the TRIM family in PAs is not well recognized. CRISPR screening explored the role of TRIM family in the cell proliferation and drug resistance in PAs. In vitro and in vivo experiments were performed to evaluate the effects of Tripartite Motif Containing 21 (TRIM21). RNA-sequencing, mass spectrometry, immunoprecipitation and ubiquitination experiments were performed to explore the molecular mechanism. NanoBiT assays were used to screen the drugs reducing TRIM21 expression. CRISPR-Cas9 screens identified that TRIM21 facilitated cell proliferation and drug resistance in PAs. Mechanistically, TRIM21 interacted with ERK1/2 through PRY-SPRY domain, leading to ERK1/2 K27-linked ubiquitination. The ERK1/2 ubiquitination promotes the interaction between ERK1/2 and MEK1/2, thereby facilitating the phosphorylation of ERK1/2. However, an excess presence of TRIM21 supressed the phosphorylation of ERK1/2 and cell proliferation via activating ERK1/2 negative feedback pathways. Importantly, TRIM21 was upregulated in dopamine-resistant prolactinomas and cabergoline-resistant MMQ cells. Furthermore, drug screening identified that Fimepinostat and Quisinostat, can reduce the protein levels of TRIM21, inhibit tumor progression, and increase drug sensitivity. TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

SURG-40. PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE

Abstract INTRODUCTION In the 2021 WHO Brain Tumor Classification, pediatric-type gliomas are distinctly categorized from their adult counterparts. The continual evolution of cancer genomics has significantly broadened the spectrum of available treatment options. Here we would like to consider surgery for pediatric low-grade gliomas. METHODS We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in pediatric patients who underwent surgery at our institute from 2002 to 2023. We discussed surgical strategies based on molecular classification. RESULTS Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification. Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytoma of the visual tract and hypothalamus, biopsy is essential for molecular diagnosis and therapeutic agent selection. 4) is mainly an epilepsy-related tumor. While their removal contributes to genetic diagnosis and epileptic seizure control, total removal may not always be deemed necessary. CONCLUSION Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.

Engineered nanoplatform mediated gas therapy enhanced ferroptosis for tumor therapy in vivo

The high glutathione (GSH) environment poses a significant challenge for inducing ferroptosis in tumor cells, necessitating the development of nanoplatforms that can deplete intracellular GSH. In this study, we developed an engineered nanoplatform (MIL-100@Era/L-Arg-HA) that enhances ferroptosis through gas therapy. First, we confirmed that the Fe element in the nanoplatform undergoes valence changes under the influence of high GSH and H2O2 in tumor cells. Meanwhile, L-Arg generates NO gas in the presence of intracellular H2O2, which reacts with GSH. Additionally, Erastin depletes GSH by inhibiting the cystine/glutamate antiporter system, reducing cystine uptake and impairing GPX4, while also increasing intracellular H2O2 levels by activating NOX4 protein expression. Through these combined GSH-depletion mechanisms, we demonstrated that MIL-100@Era/L-Arg-HA effectively depletes GSH levels, disrupts GPX4 function, and increases intracellular lipid ROS levels in vitro. Furthermore, this nanoplatform significantly inhibited tumor cell growth and extended the survival time of tumor-bearing mice in vivo. This engineered nanoplatform, which enhances ferroptosis through gas therapy, shows significant promise for ferroptosis-based cancer therapy and offers potential strategies for clinical tumor treatment.

Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC)

ObjectiveThe present study endeavors to furnish an exhaustive review of the research advancements on solid tumors harboring RET rearrangement within the Chinese context, particularly emphasizing the examination of real-world therapeutic strategies and clinical outcomes observed in individuals diagnosed with advanced non-small cell lung cancer (NSCLC). The review delves into a critical assessment of the therapeutic efficacy of targeted RET inhibitors, while also scrutinizing the diverse array of treatment modalities employed in the Chinese patient population.MethodsThe study conducted a comprehensive review of the advancements made by Chinese scholars in the realm of RET driver genes. It delved into the analysis of the incidence of RET rearrangements in solid tumors, alongside an examination of the varied treatment paradigms and their current status within China. Utilizing the RECIST 1.1 criteria, the study evaluated the therapeutic efficacy achieved in RET-positive NSCLC patients undergoing diverse treatment modalities. Furthermore, treatment-related adverse events (TRAEs) were meticulously graded following the Common Terminology Criteria for Adverse Events (CTCAE).ResultsA retrospective, multi-center, real-world analysis was conducted, encompassing 64 patients diagnosed with pathologically confirmed RET rearrangement advanced non-small cell lung cancer (NSCLC) between December 2015 and November 2023. Notably, KIF5B-RET emerged as the most prevalent RET fusion partner, accounting for 59.4% of cases. Therapeutic interventions among these patients included specific targeted inhibitors such as Pralsetinib (48.4%), chemotherapy (34.3%), multi-target inhibitors (15.6%), and one case (1.6%) involving immunotherapy combined with anti-angiogenic therapy. In terms of progression-free survival (PFS), Pralsetinib monotherapy demonstrated a median PFS of 16.03 months, outperforming chemotherapy (2.87 months; p < 0.0001), chemotherapy combined with anti-angiogenic therapy (6.90 months; p = 0.048), and multi-target inhibitors (2.50 months; p < 0.0001). Furthermore, the one-year and two-year overall survival (OS) rates for Pralsetinib monotherapy were 64.3% and 46.4%, respectively. Regarding safety, 71.0% of patients receiving Pralsetinib experienced at least one adverse event, with 45.2% classified as grade 3–4 in severity. Notably, no fatalities were attributed to adverse events. Common adverse events included hemoglobin reduction (35.5%) and neutropenia (32.3%), indicative of an overall favorable safety profile for Pralsetinib in this patient population.ConclusionThis study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC.

A Metal Coordination Polymer Nanoparticle Synergistically Re-establishes Acidosis and Enhances Chemodynamic Therapy for Glioblastoma

Background: Chemodynamic therapy (CDT) has become increasingly important as a tumor treatment strategy, which relies on intracellular acid and hydrogen peroxide to kill tumor cells by generating hydroxyl radicals (·OH) through Fenton/Fenton-like reactions. However, the weakly alkaline intracellular environment considerably caused by the efflux of lactate and H+ from glioblastoma cells is not conducive to CDT performance. Intracellular acidification induced by inhibiting the transmembrane monocarboxylate transporter 4 (MCT4) can enhance the therapeutic efficacy of CDT. Existing approaches suffer from insufficient MCT4 inhibition, involve complex drug synthesis, and have many unsatisfactory side effects.Methods: In this study, we constructed an anti-tumor nanoparticle formed by self-assembly driven by the coordination interaction of Fe3+ and α-cyano-4-hydroxycinnamate (CHC) to avoid safety issues posed by excessive modification. Fe-CHC nanoparticles were designed to decrease intracellular pH through inhibition of MCT4, which transports lactate/H+ to the extracellular space. The resulting intracellular accumulation of lactate and H+ led to fatal acidosis and promoted ·OH generated by Fenton/Fenton-like reactions with the presence of the Fe3+, thus enhancing CDT-induced tumor cell death.Results:In vitro and in vivo results revealed that Fe-CHC exerted a significant synergistic anti-tumor effect by re-establishing acidosis and enhancing CDT in glioblastoma. Furthermore, the decreased H+ outside the cells caused by the inhibition of lactate/H+ efflux hindered extracellular matrix degradation, thereby inhibiting tumor metastasis.Conclusion: Fe-CHC is an effective anti-cancer agent against glioblastoma. This study provides valuable insights for developing acid-modulating anti-tumor nanoparticles, as well as enriching and optimizing the application of CDT in tumor therapy. Statement of SignificanceOur study pioneers the Fe-CHC nanoparticle, a metal-coordination polymer that targets MCT4 in glioblastoma cells to restore intracellular acidity and synergize with Fe3+ to boost chemodynamic therapy (CDT). Unlike other studies, Fe3+ and CHC work together to maximize the therapeutic potential and safety of Fe-CHC with minimal complexity. This innovative approach not only increased the production of reactive oxygen species within tumor cells, but also hindered tumor metastasis. Our work has important scientific implications for tumor microenvironment regulation and the application of CDT, and will provide a promising pathway for the treatment of aggressive cancers and attract a wide audience through its scientific implications.

Natural diterpene carrier-free hydrogel enhances antigen presentation and intensifies T cell activation for tumor immunotherapy

Although immunotherapy has revolutionized cancer treatment, the low immunogenicity, insufficient T cells intratumoral infiltration and defective antigen presentation in the “cold” tumor microenvironment limit its clinical application. To address this challenge, enlightened by the clinical combined application of antitumor herb medicines, we developed a carrier-free hydrogel KEEM by integrating multiple natural active lipophilic components with manganese ions into a natural co-assembled ternary system. The KEEM hydrogel induced the formation of hydroxyl radicals by Fenton-like reactions, leading to apoptosis, while simultaneously inducing tumor cell ferroptosis through the system xc−-GSH-GPX4 axis. Subsequent release of damage-associated molecular patterns (DAMPs) proved the emergence of immunogenic cell death (ICD). Additionally, manganese ions could directly activate the cGAS-STING pathway, further amplifying the immunostimulatory effects. This synergistic effect promoted dendritic cell maturation thus enhancing antigen presentation, and mediating the change of tumor microenvironment (TME) from “cold” to “hot”. In hepatoma ascites and melanoma models, KEEM combined with immune checkpoint blockade and adoptive T cell therapy respectively demonstrated promising anti-tumor effects in vivo, meanwhile showing excellent biocompatibility and biosafety. Thus, the combination of this multi-diterpenoids carrier-free hydrogel with immunotherapy offers a new strategy for clinical immune-refractory tumor treatment.

Identification of biomarkers related to Escherichia coli infection for the diagnosis of gastrointestinal tumors applying machine learning methods

BackgroundEscherichia coli (E. coli) is a part of normal gastrointestinal microbiota but it could also cause human gastrointestinal diseases. Understanding the mechanism of E. coli in the progression of gastrointestinal tumors can provide novel prevention and treatment strategies for gastrointestinal tumors. MethodsThe E. coli infection score was calculated by single sample GSEA (ssGSEA). Weighted correlation network analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify genes related to E. coli infection in gastrointestinal tumors. Hub genes were selected by machine learning methods to establish a diagnostic model. The diagnostic performance of the model was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC) and validated in three external datasets. After determining the biomarkers, immune infiltration analysis and GSEA were further performed. The mRNA expressions of the biomarkers in stomach adenocarcinoma (STAD) cells and the invasion and migration of the tumor cells were detected by conducting in vitro experiments. ResultsThe E. coli infection score was lower in tumor samples than in normal samples. Eight hub genes were selected from a total of 28 genes associated with E. coli-related dysbiosis in gastrointestinal tumors to establish an accurate diagnostic model. The AUC values of PRKCB and IL16 were all greater than 0.7 in three external datasets and the mRNA expression pattern was consistent with TCGA cohort, therefore PRKCB and IL16 were selected as the diagnostic biomarkers. PRKCB and IL16 exhibited significant positive correlations with most immune cells, and inflammation-related pathways were activated in the high expression groups of PRKCB and IL16. Moreover, IL16 was high-expressed but PRKCB was low-expressed in STAD cells, and silencing IL16 suppressed the invasion and migration of STAD cells. ConclusionsOverall, we identified and validated 8 robust genes related to E. coli applying bioinformatics and machine learning algorithms, providing theoretical foundations for the relationship between E. coli-related dysbiosis and gastrointestinal tumors.

Thermo-responsive gold nanorod vesicles for combined NIR-II photothermal therapy and chemotherapy of solid tumors

Photothermal therapy (PTT) is a promising treatment strategy for malignant tumors. Photothermal agents which can achieve efficient photothermal conversion in the NIR-II region plays crucial roles in this remedy. Here, we report one type of thermo-responsive gold nanorod vesicles USGRV-17-AAG for combined NIR-II photothermal therapy and chemotherapy of solid tumors. The nanovesicles are formed by self-assembly of gold nanorods modified with amphiphilic polymers (PEG45-b-PS450) and UCST-type polymers (P(AAm-co-AN)), and are loaded with the heat shock protein inhibitor 17-AAG. Upon 1064 nm laser irradiation, USGRV-17-AAG exhibits a high photothermal conversion efficiency (65.1 %) and thus can achieve temperature responsive release of tanespimycin (17-AAG), an inhibitor of HSP90. The combination of NIR-II photothermal therapy and chemotherapy can effectively eliminate tumor cells and inhibit the expression of HSP90. Intravenous injection of USGRV-17-AAG followed by 1064 nm laser irradiation revealed efficacious tumor ablation of tumor-bearing mice, with a tumor growth inhibition rate of 98.86 %. Therefore, USGRV-17-AAG can produce efficient anti-tumor effects and provides an alternative approach to the treatment of malignant tumors. Statement of significancePhotothermal conversion agents (PTAs) based on the near-infrared II (NIR-II) window are currently attracting significant attention for their promising development and diverse applications. In this study, thermosensitive drug-loaded nanovesicles, USGRV-17-AAG, were designed to enable NIR-II photothermal therapy in combination with chemotherapy. These nanovesicles were loaded with the heat shock protein 90 (HSP90) inhibitor 17-AAG, which effectively inhibits HSP90 expression and enhances the therapeutic efficacy of photothermal treatment. Additionally, USGRV-17-AAG exhibited efficient photothermal conversion (65.1 %) under 1064 nm laser irradiation and enabled temperature-responsive drug release through the action of surface-modified upper critical solution temperature (UCST) polymers. This nanocarrier, with enhanced NIR-II photothermal therapy, might offer a promising solution for anti-tumor treatment.

Investigating the therapeutic potential of Elemene emulsion injection as an adjuvant for chimeric antigen receptor T cell therapy: Transcriptome analysis and experimental validation

IntroductionElemene emulsion injection (EEI) is prepared from monomers extracted from Chinese medicine. It has been used as an adjuvant anti-tumor medication in clinical settings for over 30 years. Chimeric antigen receptor T cells (CAR-T) are a successful immunotherapy strategy for tumor treatment. This study aimed to investigate the role and potential mechanisms of EEI as an adjuvant to CAR-T cells for tumor treatment. MethodsCCK8 staining was utilized to detect the effect of EEI on tumor cell viability. CD19 CAR-T and Trop2 CAR-T cells were constructed, and EEI was added to the experimental system. Untreated CAR-T cells served as a control group. After co-cultured with tumor cells, the effect of EEI on CAR-T cell function was assessed. Flow cytometry, luciferase reporter gene, IncuCyte, and cytokine assays were used to evaluate the effects of the EEI on CAR-T cell cytotoxicity and phenotype in vitro. RNA sequencing was utilized to analyze the effect of EEI on CAR-T cell gene expression. Network pharmacology was applied to predict potential EEI therapeutic targets for CRS, which were verified via a THP-1 macrophage inflammation model. ResultsEEI enhanced the cytotoxicity of CAR-T cells against tumors. RNA-seq revealed that EEI modulated cytokine activity and Th17 cell differentiation in CAR-T cells. Subsequent experiments confirmed that the proportion of CD4+ T cells in CAR-T cells increased. The secretion of cytokines was greatly reduced under the effect of EEI. In the THP-1 macrophage inflammation model, EEI significantly reduced the levels of cytokines associated with inflammation induced by CAR-T cells. ConclusionsThis research proposed and tested a combination therapy involving EEI and CAR-T cells. The combination of CAR-T cells with EEI for tumor immunotherapy may enhance the clinical efficacy while providing synergistic effects and reducing toxicity. FundingScientific Research Startup Funds for High-level Talents from Beijing University of Chinese Medicine (Grant No. 9011451310032)

Compact Molecular Conformation of Prodrugs Enhances Photocleaving Performance for Tumor Vascular Growth Inhibition.

Highly spatiotemporal-resolved photomodulation demonstrates promise for investigating key biological events in vivo and in vitro, such as cell signaling pathways, neuromodulation, and tumor treatment without side effects. However, enhancing the performance of photomodulation tools remains challenging due to the limitations of the physicochemical properties of the photoactive molecules. Here, a compact, stable intramolecular π-πstacking conformation forming between the target molecule (naproxen) and the perylene-based photoremovable protecting group is discovered to confine the motion of the photolabile bond and then enhance the photocleavage quantum yield. In conjunction with a red-absorbing photosensitizer, the photocleavage wavelength is extended to the red region via triplet-triplet annihilation. In particular, the triplet lifetime of the prodrug can be extended via the linked steric hindrance to improve the conversion yield via TTA. Using the new photomodulation tool, it is precisely photoreleased cyclooxygenase-2 inhibitors for tumor vascular growth suppression in vivo. In combination with cisplatin, over 90% efficient inhibition of malignant breast tumors is observed via the synergistic tumor treatment strategy. These findings provide a new concept for the rational design of efficient photocleavage and have implications for photomodulating cell signaling pathways in tumor therapy, as well as laying a solid foundation for the development of phototherapeutic approaches.

Decoding tumor-fibrosis interplay: mechanisms, impact on progression, and innovative therapeutic strategies.

Malignant tumors are a category of diseases that possess invasive and metastatic capabilities, with global incidence and mortality rates remaining high. In recent years, the pivotal role of fibrosis in tumor progression, drug resistance, and immune evasion has increasingly been acknowledged. Fibrosis enhances the proliferation, migration, and invasion of tumor cells by modifying the composition and structure of the extracellular matrix, thereby offering protection for immune evasion by tumor cells. The activation of cancer-associated fibroblasts (CAFs) plays a significant role in this process, as they further exacerbate the malignant traits of tumors by secreting a variety of cytokines and growth factors. Anti-fibrotic tumor treatment strategies, including the use of anti-fibrotic drugs and inhibition of fibrosis-related signaling pathways such as Transforming Growth Factor-β (TGF-β), have demonstrated potential in delaying tumor progression and improving the effectiveness of chemotherapy, targeted therapy, and immunotherapy. In the future, by developing novel drugs that target the fibrotic microenvironment, new therapeutic options may be available for patients with various refractory tumors.

T1/T2 Proportional Magnetic Resonance Nanoprobe Monitoring Tumor Autophagy during Chemotherapy.

Autophagy leads to cellular tolerance of the therapeutic pressure of chemotherapeutic drugs, resulting in treatment resistance. Therefore, the effective monitoring of the autophagy status of tumors in vivo and the regulating of the autophagy level are crucial for improving the efficacy of chemotherapy. In this work, we grafted nitroxide radicals onto the surface of iron oxide nanoparticles (Fe3O4 NPs) using dendrimer polymers, yielding Fe3O4-NO· NPs that are responsive to reactive oxygen species (ROS) and possess enhanced T1 and T2 signal capabilities in a magnetic resonance imaging (MRI) measurement. The ROS in tumor cells generated by autophagy quenches the nitroxide radicals, thereby weakening the T1 signal. In contrast, Fe3O4 NPs are unaffected by intracellular ROS, leading to a stable T2 signal. By comparing the intensity ratio of T1 to T2 in Fe3O4-NO· NPs, we can evaluate the in vivo autophagy status within tumors in real time. It also revealed that Fe3O4-NO· NPs loaded with doxorubicin (Dox) and combining the autophagy inhibitor exhibited high antitumor activity in cells and tumor-bearing mice. This system, which combines real-time monitoring of tumor cell autophagy with the delivery of chemotherapeutic drugs, provides an innovative and effective strategy for tumor treatment with potential clinical application prospects.

Injectable hydrogels for Fenton-like Mn2+/Fe2+ delivery with enhanced chemodynamic therapy prevent osteosarcoma recurrence and promote wound healing after excision surgery

Local recurrence of osteosarcoma and wound healing after excision surgery are major challenges in clinical research. The present anti-tumor treatments could inhibit normal tissues, resulting in difficulties in surgical wound healing. In this study, we constructed an injectable hydrogel as a platform to co-deliver MnO2 nanoparticles and ferrocene Fc, termed as (MnO2/Fc)@PLGA for osteosarcoma treatment and wound healing after excision. By simple local injection, the hydrogel could form a protective barrier on the surgical wound after osteosarcoma excision, which could promote wound healing and steady release of MnO2/Fc nanoparticles. The released MnO2/Fc might undergo the Fenton reaction through Mn2+/Fe2+ to inhibit osteosarcoma cells with chemodynamic therapy (CDT). Furthermore, MnO2 could catalyze endogenous H2O2 to produce O2, which eliminates the adverse effects of H2O2 and remodels the hypoxic state in the local lesions. The increased O2 facilitated surgical wound healing and anti-tumor effects by regulating the hypoxia inducible factor-1 functions. In conclusion, (MnO2/Fc)@PLGA hydrogel could effectively prevent local recurrence of osteosarcoma and promote wound healing after excision surgery, thereby providing a novel strategy for tumor treatment and tissue repair.

Priming of cancer-immunity cycle by alleviating hypoxia-induced ferroptosis resistance and immunosuppression

Stimulating a robust cancer-immunity cycle (CIC) holds promising potential for eliciting potent and enduring immune responses for cancer immunotherapy. However, designing a therapeutic nanomaterial capable of both enhancing tumor immunogenicity and mitigating immunosuppression is challenging and often associated with complicated design paradigms and immune-related adverse effects. Herein, a multienzyme-mimetic alloy nanosheet incorporating palladium (Pd) and iron (Fe) is developed, which can prime effective CIC by overcoming ferroptosis resistance for enhancing tumor immunogenicity and reprograming the tumor microenvironment for enhanced second near-infrared (NIR-II) photoimmunotherapy. The nanosheets accumulate in tumors when administered intravenously and counteract hypoxia through catalase-like oxygen production and subsequent reduction of hypoxia-inducible factor-1α, M2-like macrophages, regulatory T-cell, and programmed death-ligand 1 (PD-L1) expression. The surface plasmon resonance of the nanosheets enables NIR-II phototherapy and photoacoustic imaging, coupling with its ferroptosis and tumor microenvironment reprogram properties to synergize with anti-PD-L1 checkpoint blockade therapy to achieve satisfactory antitumor outcome. This study offers a strategy for localized tumor treatment and boosting the CIC through a straightforward and inexpensive nanomaterial design.

NRG1 Fusions in NSCLC: Being eNRGy Conscious.

Fusions in neuregulin 1 (NRG1) are rare oncogenic drivers that occur across a number of tumor types, including non-small cell lung cancer (NSCLC). NRG1 has an EGF-like domain that serves as a ligand for HER3 receptors, inducing heterodimerization, usually with HER2, and subsequent activation of oncogenic downstream signaling pathways. Emerging evidence suggests that NSCLC harboring NRG1 fusions do not respond as well to standard therapeutic options including chemotherapy and immunotherapy, and prognosis is poor. Novel treatment approaches targeting the HER2/HER3 pathway are under investigation. Here, we discuss the biology and detection of NRG1 fusions in NSCLC and promising targeted treatment strategies for tumors harboring the mutation.

A glutathione-activated bismuth-gallic acid metal-organic framework nano-prodrug for enhanced sonodynamic therapy of breast tumor

Sonodynamic therapy is a promising, noninvasive, and precise tumor treatment that leverages sonosensitizers to generate cytotoxic reactive oxygen species during ultrasound stimulation. Gallic acid (GA), a natural polyphenol, possesses certain anti-tumor properties, but exhibits significant toxicity toward normal cells, limiting its application in cancer treatment. To overcome this issue, we synthesized a bismuth-gallic acid (BGA), coordinated metal–organic framework (MOF) nano-prodrug. Upon encountering glutathione (GSH), BGA gradually dissociated and depleted GSH, releasing GA, which had anti-tumor effects. As an MOF with semiconductor properties, BGA primarily produced superoxide anion radical upon ultrasound excitation. After the release of GA, GA generated superoxide anion radical and further produced high toxic singlet oxygen under ultrasound stimulation, while further oxidizing and consuming GSH, enhancing sonocatalytic performance. Additionally, the released GA induced cell cycle arrest, ultimately leading to apoptosis. Our results revealed that BGA, as a GSH-activated, metal-polyphenol MOF nano-prodrug, showed potential for use in breast tumor sonodynamic therapy, providing a novel strategy for precise tumor treatment.

Machine learning-based individualized survival prediction model for prognosis in osteosarcoma: Data from the SEER database.

Patient outcomes of osteosarcoma vary because of tumor heterogeneity and treatment strategies. This study aimed to compare the performance of multiple machine learning (ML) models with the traditional Cox proportional hazards (CoxPH) model in predicting prognosis and explored the potential of ML models in clinical decision-making. From 2000 to 2018, 1243 patients with osteosarcoma were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Three ML methods were chosen for model development (DeepSurv, neural multi-task logistic regression [NMTLR]) and random survival forest [RSF]) and compared them with the traditional CoxPH model and TNM staging systems. 871 samples were used for model training, and the rest were used for model validation. The models' overall performance and predictive accuracy for 3- and 5-year survival were assessed by several metrics, including the concordance index (C-index), the Integrated Brier Score (IBS), receiver operating characteristic curves (ROC), area under the ROC curves (AUC), calibration curves, and decision curve analysis. The efficacy of personalized recommendations by ML models was evaluated by the survival curves. The performance was highest in the DeepSurv model (C-index, 0.77; IBS, 0.14; 3-year AUC, 0.80; 5-year AUC, 0.78) compared with other methods (C-index, 0.73-0.74; IBS, 0.16-0.17; 3-year AUC, 0.73-0.78; 5-year AUC, 0.72-0.78). There are also significant differences in survival outcomes between patients who align with the treatment option recommended by the DeepSurv model and those who do not (hazard ratio, 1.88; P < .05). The DeepSurv model is available in an approachable web app format at https://survivalofosteosarcoma.streamlit.app/. We developed ML models capable of accurately predicting the survival of osteosarcoma, which can provide useful information for decision-making regarding the appropriate treatment.