Therapeutic nucleic acid (TNA)-based gene silencing strategies, such as antisense oligonucleotides (ASOs), have been explored for cancer treatment. However, no ASO-based anticancer drugs are currently available, largely because of limited therapeutic efficacy. Conventional ASO-based cancer therapies typically target oncogenes or cancer-associated genes because constitutively active ASOs may also damage normal tissues. We hypothesized that this limitation can be overcome by conditionally activating ASOs only in response to cancer-specific biomarkers. In this paradigm, therapeutic efficacy is determined by the potential of the released ASO rather than by the cancer specificity of its target, allowing any gene essential for cell survival to serve as a target. Our aim was to identify the most cytotoxic ASO sequences for cancer cells. We designed 37 ASOs targeting 13 candidate genes and evaluated them in human ovarian adenocarcinoma (SKOV3) and lung adenocarcinoma (A549) cell lines. An ASO targeting DARS1 exhibited the strongest activity, inducing apoptotic cell death in both cell types. Additional ASOs targeting DYNC1I2 and EIF2S3 were identified as effective candidates in SKOV3 and A549 cells, respectively. Importantly, the selected ASOs exhibited low toxicity toward the tested noncancerous cell line. These findings identify DARS1, DYNC1I2, and EIF2S3 as promising targets for marker-dependent ASO-based cancer therapy.

Leukemia cutis is a rare cutaneous manifestation of acute myeloid leukemia, most frequently associated with monocytic differentiation. Darier's sign, a wheal-and-flare response classically linked to cutaneous mastocytosis, has only rarely been reported in leukemia cutis and may represent a diagnostic pitfall. We report a pediatric patient diagnosed with acute myeloid leukemia that developed multiple violaceous papules on the extremities and trunk. Mechanical stimulation induced erythema and edema consistent with a positive Darier's sign. Histopathological examination revealed dermal infiltration by myeloperoxidase (MPO)-positive leukemic blasts, confirming leukemia cutis. Bone marrow aspiration and flow cytometry were compatible with acute monoblastic leukemia (AML-M5). This case highlights that Darier's sign may rarely occur in leukemia cutis and should not be considered exclusive to mastocytosis.

BACKGROUND: The clinical characteristics of BRCA1 and BRCA2 (BRCA) deleterious alterations in advanced prostate cancer-considering age, family history, co-occurring gene alterations, and variant type-remain incompletely understood in patients undergoing tumor-only panel testing. MATERIALS AND METHODS: We analyzed 2,815 patients who underwent comprehensive cancer genomic profiling (CGP) using a tissue-based tumor-only panel from December 2020 to November 2024. Eligible patients had metastatic prostate cancer resistant to standard therapies or androgen-indifferent prostate cancer, including neuroendocrine prostate cancer. Data were obtained from the Center for Cancer Genomics and Advanced Therapeutics, a nationwide CGP database in Japan. RESULTS: Median age at CGP testing was 72 years (range 23-93 years). BRCA deleterious alterations were detected in 428 patients (15.2%), decreasing with age: 24.2% (< 50 years), 25.4% (50-59 years), 16.3% (60-69 years), 14.3% (70-79 years), and 9.3% (≥ 80 years). A family history of breast or ovarian cancer independently predicted BRCA alterations (odds ratio 1.901 and 3.016; both p < 0.05). RB1 alterations and MYC amplification were significantly enriched as co-occurring alterations in BRCA2 (6.9% vs. 14.9%, 15.4% vs. 23.1%; both p < 0.05). Stratified by BRCA2 variant type, patients with homozygous deletion (HD) had longer overall survival than those with truncating alterations following olaparib treatment (median 30.6 vs. 16.9 months; hazard ratio 0.373; 95% CI 0.220-0.633). CONCLUSIONS: In advanced, therapy-resistant prostate cancer, BRCA deleterious alterations were more frequent in younger patients and those in with a family history of breast and ovarian cancer. BRCA2 HD was significantly associated with a favorable response to olaparib.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) rarely responds to immune checkpoint blockade despite clear evidence that androgen receptor (AR) signaling intersects with tumor immunity. The view that androgen deprivation uniformly enhances antitumor immunity does not explain the repeated failure of immunotherapy combinations in biomarker-unselected populations. METHODS: This narrative review synthesizes mechanistic, translational, and clinical evidence and organizes it by cellular compartment, treatment-associated immune state, clinical trial strategy, and biomarker readiness. RESULTS: AR-directed therapy produces context-dependent, compartment-specific immune remodeling. It can alter tumor antigen visibility, thymic output, and T-cell trafficking, while myeloid cytokines and metabolites, cancer-associated fibroblasts, and metastatic niches sustain AR reactivation, T-cell dysfunction, and immune exclusion. These effects are better understood as heterogeneous tumor-immune states than as a fixed treatment window. Randomized phase III trials combining checkpoint blockade with AR pathway inhibitors, PARP inhibitors, or chemotherapy have not improved overall survival in unselected mCRPC, and dual-checkpoint blockade has shown limited activity with substantial toxicity. Deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) disease is currently the only clinically validated enrichment factor for checkpoint blockade in mCRPC, although this subgroup is uncommon. Composite signatures remain investigational. CDK12, homologous-recombination repair alterations, isolated tumor mutational burden-high disease, PD-L1, and AR-V7 are not independently validated selection markers. T-cell engagers have produced early PSA and radiographic responses by providing a distinct route to tumor-T-cell contact. Their development must balance this activity against cytokine-release syndrome, antigen heterogeneity, variable therapeutic windows, and the lack of comparative evidence. CONCLUSIONS: Progress requires trials that define the relevant tumor-immune state, match treatment to the dominant resistance mechanism, and prospectively test biomarker-treatment interaction. In current practice, dMMR/MSI-H remains the only validated enrichment factor for checkpoint blockade in mCRPC; all other proposed markers and T-cell engager strategies require prospective validation of treatment interaction.

BACKGROUND: A higher ratio of IGF-1:IGF binding protein 1 (IGFBP1) was associated with improved prognosis in the CHAARTED trial of docetaxel in participants with metastatic hormone-sensitive prostate cancer (mHSPC). The ENZAMET trial demonstrated the survival benefit of adding enzalutamide to androgen deprivation therapy (ADT) in mHSPC, and included participants who also received docetaxel as standard of care. The aim of this study was to validate the association between levels of circulating IGF-1 and IGFBP1 and survival of ENZAMET participants. METHODS: IGF-1 and IGFBP1 levels were measured in baseline plasma from 845 ENZAMET participants, and associations with clinical progression-free survival (cPFS) and overall survival (OS) were assessed as a post-hoc analysis. RESULTS: A high baseline plasma ratio of IGF-1:IGFBP1 (upper two tertiles) was associated with improved OS (HR 0.75, p 0.008) and improved cPFS (HR 0.82, p 0.034) compared to the lowest tertile. IGF-1:IGFBP1 was not predictive of enzalutamide or docetaxel benefit (no significant interaction with treatment arm or docetaxel use). In participants in the enzalutamide arm, IGF-1:IGFBP1 was an independent predictor for OS and cPFS in bivariable analysis with docetaxel use. The rate of high volume disease was similar in patients with lower IGF-1:IGFBP1 ratio and those with high ratio (~50%). CONCLUSIONS: This analysis demonstrated a consistent association of improved prognosis with high IGF-1:IGFBP1 in mHSPC, but did not identify which participants benefited from docetaxel when treated with enzalutamide.

Prevention of breast cancer is feasible because many risk factors for this malignancy are known (e.g., family history, reproductive factors, etc.). Medicinal plants and/or their bioactive phytochemicals are attractive for the prevention of early onset of breast cancer due to their generally favorable safety profile. Root extract of Withania somnifera (Ashwagandha) is a key ingredient in Ayurvedic medicine practiced in India for thousands of years. Preclinical research has established that withaferin A (WA) is primarily responsible for the anticancer effect of Ashwagandha. At cellular level, WA treatment inhibits the growth of human breast cancer cells by causing G/M phase cell cycle arrest and apoptosis induction and suppressing the self-renewal of breast cancer stem-like cells. On the other hand, normal mammary epithelial cells are resistant to apoptosis induction by WA, which is a desirable characteristic of cancer preventive interventions. More importantly, WA administration prevents luminal type, human epidermal growth factor receptor 2-driven, and basal-like breast cancer development in rodents without causing any side effects. This review article not only succinctly summarizes preclinical evidence for anticancer effects of WA but also conceptualizes on high-risk women and men who may benefit from Ashwagandha intervention for prevention of early onset of breast cancer or prevention of bone metastasis of breast cancer.

Immune checkpoint blockade has improved outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but reliable biomarkers for predicting therapeutic response remain limited. Tumor-reactive T-cell states are increasingly recognized as critical determinants of antitumor immunity; however, progression-associated T-cell programs that reflect tumor evolution and predict immunotherapy benefit remain insufficiently characterized. We integrated single-cell transcriptomic and T-cell receptor (TCR) sequencing data from HPV-negative HNSCC progression models to identify T-cell genes associated with tumor progression and TCR-supported immune states. Candidate genes were further refined using pretreatment immunotherapy cohorts, and a five-gene signature (HNSC-TstcSig) was established using survival and response-associated analyses. The predictive performance of HNSC-TstcSig was evaluated across multiple immunotherapy cohorts, including HNSCC and melanoma data sets. Single-cell transcriptomic analyses, spatial transcriptomic analysis, and multiplex immunofluorescence were performed to characterize the biological features of HNSC-TstcSig-associated immune states. In addition, machine learning-based survival modeling was conducted to identify genes shared between immunotherapy response and natural prognosis. HNSC-TstcSig, consisting of GBP2, HAVCR2, ETV7, ICOS, and IL2RA, showed consistent associations with immunotherapy response across multiple cohorts and reflected an immune-inflamed tumor microenvironment characterized by enhanced immune infiltration, T-cell activation, and immune checkpoint-related programs. Single-cell analyses revealed that HNSC-TstcSig genes were predominantly enriched in activated CD8 T-cell populations and were associated with cytotoxic and inflammatory immune states. Among the signature genes, ICOS showed consistent associations with CD8 T-cell activation, cytotoxicity, and immune checkpoint-related features. Network perturbation analysis further suggested that ICOS was connected with transcriptional programs involved in T-cell functional regulation. Spatial transcriptomic analysis and multiplex immunofluorescence further supported the association between ICOS-related immune features and tumor immune activity at the tissue level. Furthermore, a machine learning-derived natural prognostic model identified ICOS as a shared gene linking immunotherapy response and survival outcomes. We developed a progression-associated T-cell signature, HNSC-TstcSig, that predicts immunotherapy response and reflects immune-active tumor states in HNSCC. Our findings suggest that ICOS is associated with a tumor-reactive CD8 T-cell state characterized by cytotoxic activity and immune checkpoint-related features, providing a potential biomarker for immune stratification and a framework for understanding T-cell states associated with therapeutic benefit.

Hypertrophic scar (HS) is a recurrent and inflammatory dermal fibrotic disorder, characterized by abnormal fibroblast proliferation and excessive extracellular matrix (ECM) deposition. Affecting over 310 million patients worldwide, while effective strategies to halt progression remain lacking. The TGF-β-mediated fibrotic cascade is the central driver of HS, and siRNA-based therapeutics offer a promising gene-level intervention owing to their high sequence specificity and low off-target risk. However, siRNA translation is limited by rapid degradation, poor transfection, insufficient targeting, and the dense scar barrier that restricts noninvasive delivery. Proteomic analysis revealed that hypertrophic scar fibroblasts (HSFs) exhibit enhanced bioadhesion and protein-binding functions, with Thy-1 membrane glycoprotein highly and specifically expressed, providing a target for HSFs-active delivery. We hybridized HSFs membranes with cationic transfersomes using ultrasonic co-extrusion and achieved efficient loading of TGF-β1 siRNA through electrostatic self-assembly. This membrane-hybridized platform enabled multipathway transdermal delivery of siRNA via intercellular transport, transcytosis, and skin appendageal routes, while improving transfection, immune evasion, and homotypic targeting. Studies demonstrated efficient silencing of TGF-β1, suppression of α-SMA, ECM deposition, and pro-inflammatory cytokine release, thereby mitigating fibrotic progression. The system provides an innovative strategy for transdermal targeted siRNA therapy of HS and other skin diseases requiring genetic intervention.

While significant advances have been made in maintaining stem cell pluripotency, the successful establishment of embryonic stem cells (ESCs) from various animal species in vitro remains challenging. This highlights the need for further optimization of culture conditions. Through compound library screening, we identified Danofloxacin, a small molecule, as a promoter of mouse ESC stemness. Danofloxacin enhances the formation of undifferentiated colonies and the generation of chimeric mice. Mechanistically, it suppresses HDAC1 expression and activity, resulting in increased acetylation of histone H3 at lysines 9 (H3K9ac) and 27 (H3K27ac), which in turn upregulates the expression of Tert and Prdm10. Functional assays revealed that overexpressing Tert or Prdm10 mimics Danofloxacin's effect on ESC self-renewal, whereas knockdown of either gene disrupts this process. Moreover, the elevated levels of H3K9ac and H3K27ac activate the PI3K/AKT and HIF-1α signaling pathways, both of which contribute to the transcriptional upregulation of Tert and Prdm10. These findings offer new insights into the pluripotency regulatory network and propose potential strategies for isolating ESCs from other species in vitro.

Adoptive cell therapy (ACT) remains challenging in solid tumors, where poor tumor infiltration, metabolic heterogeneity, and an immunosuppressive tumor microenvironment (TME) constrain therapeutic efficacy. Here, we developed magnetically and metabolically programmed macrophage-based immune microrobots (immunobots) for active solid tumor immunotherapy. The immunobots are constructed by loading bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS)-modified Janus L1-FePt magnetic microrollers (LMRs), which function both as an external magnetic actuation unit and as biochemical regulators that program macrophages into an anti-tumor phenotype. Optimized LMR loading endows the immunobots with robust propulsion, retention under flow, and enhanced barrier penetration. LMRs drive M1-like polarization through LPS-induced inflammatory activation and FePt-derived labile iron-amplified oxidative stress, leading to altered iron homeostasis, elevated reactive oxygen species (ROS), and enhanced NF-κB signaling. Functionally, immunobots induce ferroptosis-associated immunogenic cell death (ICD) in tumor cells. In vivo, magnetically guided immunobots suppress tumor growth through coordinated remodeling of the tumor immune landscape, including tumor-associated macrophage (TAM) reprogramming, dendritic cell maturation, and enhanced CD8 T cell activation. Collectively, this work establishes a magnetically guided and metabolically programmed microrobotic immunotherapy strategy for overcoming the physical, metabolic, and immunological barriers that limit cellular therapy in solid tumors.

mRNA-encapsulated lipid nanoparticles (LNPs) have been used to develop vaccines and therapeutics since the COVID-19 pandemic, and clinical studies have demonstrated therapeutic benefits of mRNA vaccines for various cancers. However, current LNP formulations still require functional modifications to tailor them for therapeutic and vaccine applications. Recently, fifth component-incorporated LNPs were developed to finely tune their functionality, including immunogenicity and organ-targeting ability. Here, biphenyl-structured amphiphilic PDL1 inhibitors are employed as a fifth component to modify LNPs. Amphiphilic PDL1 inhibitor-incorporated, ALC0315-based LNPs show higher lymph node targeting, with a 6.94-fold increase in mRNA expression in the inguinal lymph node, thereby improving lymph node expansion and immune cell infiltration and, consequently, inducing greater mRNA vaccine efficacy. Furthermore, a consistent lymph node-targeting effect of the fifth component-containing LNP was observed across studies using the SM102-based LNP formulation, suggesting its universality. In conclusion, this study demonstrates that PDL1 inhibitor-incorporated fifth-component LNP serves as a next-generation platform for mRNA vaccines.

Hyperactivated M1 macrophages with excessive reactive oxygen species (ROS) exacerbate intestinal inflammation, driving the progression of inflammatory bowel diseases (IBDs), for instance, ulcerative colitis. Current standard treatments for IBDs show limited efficacy and off-target side effects. Herein, we develop an oral, drug-free hyaluronic acid (HA)-based therapeutics that could self-assemble in aqueous solution, accumulate in inflamed colons and attenuate M1-like activation, thereby rebalancing the colonic immune landscape. Such drug-free therapeutics are generated by the conjugation of unsaturated fatty acids to HA via dynamic covalent boronate-catechol ester bonds. Mechanistically, the nano-assemblies (termed uhNAs) effectively scavenge ROS, dampen NF-κB signaling, and diminish pro-inflammatory cytokines in M1-like phenotypes. In DSS-induced acute colitis, oral uhNAs treatment elicits significant decreases in M1-like macrophages, CD8 T cells, and neutrophils with concomitant increases in Tregs. In chronic and relapsing DSS colitis, uhNAs also confer robust protection, supporting sustained colonic immune remodeling during recurrent intestinal inflammation. Single-cell RNA-sequencing corroborates these shifts and maps the myeloid, B and T-cell programs, highlighting the downregulated inflammatory responses following uhNAs treatment. Notably, uhNAs-OA outperform physical HA (or HA-PBA)/oleic-acid mixtures, and two clinically established IBD drugs (5-aminosalicylic acid and dexamethasone), protecting mice models against both acute and chronic colitis.

5-Methylcytosine (mC) is a vital RNA modification that regulates mRNA stability, splicing, and nuclear export. As a key mC reader, ALYREF promotes tumorigenesis across various cancers; however, its precise role in endometrial cancer (EC) remains unknown. ALYREF expression and clinical significance in EC were evaluated using bioinformatics and immunohistochemistry. In vitro and in vivo assays examined its functional roles. Integrated multi-omics (RNA-seq, RIP-seq, and mC-BS-seq) and rescue assays identified downstream targets. RNA stability, nuclear-cytoplasmic fractionation, site-directed mutagenesis, dual-luciferase, immunofluorescence, and Western blotting were performed to elucidate the underlying mechanisms. ALYREF is significantly upregulated in EC and serves as an independent prognostic factor for poor overall survival. Functional studies demonstrated that ALYREF markedly promotes EC cell proliferation, migration, invasion, and tumor growth. Mechanistically, XRCC6 was identified as a direct functional target. ALYREF enhances XRCC6 mRNA stability in an mC-dependent manner, subsequently activating canonical Wnt/β-catenin signaling to drive EC progression. Our findings reveal that ALYREF functions as a potential oncogenic driver in EC. The ALYREF-mC-XRCC6 axis accelerates EC progression via Wnt/β-catenin signaling, highlighting a promising therapeutic target.

Microwave ablation (MWA) for large hepatocellular carcinoma (HCC) is frequently compromised by non-uniform thermal distribution and immunosuppressive niche formation. To address these challenges, we engineered an injectable bimodal nanodepot (TCPD) via catalytic crosslinking of dopamine-modified hyaluronic acid by microwave thermal converter cesium-doped Prussian blue, enabling co-delivery of glutaminase 1 inhibitor Telaglenastat and sonosensitizer Chlorin e6. Under combined MWA and ultrasound irradiation, TCPD nanodepot disrupts cellular antioxidant defenses and bioenergetic pathways through glutaminolysis-TCA cycle blockade, metabolically sensitizing large tumors to spatially complementary sono-thermal ablation and enabling complete treatment coverage. This multimodal intervention induces multiple subcellular stresses, including mitochondrial and endoplasmic reticulum dysfunction, genotoxicity, and NAD depletion, which converge to facilitate PANoptosome assembly and immunogenic PANoptosis while activating the cGAS-STING pathway. Subsequent release of damage-associated molecular patterns and immunoregulatory cytokines promotes dendritic cell maturation, M1 macrophage polarization, and T lymphocyte infiltration, ultimately reprogramming the immunosuppressive microenvironment toward an immune‑activated niche. Integration with anti-PD-1 therapy further reinvigorates cytotoxic T lymphocytes and establishes antitumor immune memory to suppress tumor progression and metastasis, offering a multimodal therapeutic strategy for large HCC.

Accurate and in situ detection of uracil-DNA glycosylase (UDG) is crucial for clinical diagnosis and prognosis assessment. However, conventional methods show low accuracy, limited sensitivity, and off-target signal leakage due to flawed signal input/output and amplification mechanisms. Therefore, an engineered allosteric biosensor (UUU-DZ-tFNA) was developed, in which UDG specifically recognizes and activates a DNAzyme to achieve signal cycle amplification in a sequentially activatable mode. Experimental results demonstrated that UUU-DZ-tFNA enables rapid, highly sensitive (LOD = 0.025 mU/mL), and specific detection of UDG. In addition, UUU-DZ-tFNA enables in situ molecular imaging of UDG at both the neuroblastoma (NB) cellular and animal levels, as well as precise in situ detection of UDG in plasma exosomes from NB patients. In particular, the non-invasive risk stratification model for NB developed using machine learning based on exosomal UDG and clinical multidimensional indicators, including MYCN amplification status, International NB Risk Factors (IDRFs), neuron-specific enolase (NSE), and lactate dehydrogenase (LDH), showed excellent discriminatory ability, with 85.7% sensitivity, 100.0% specificity, and 92.8% accuracy. UUU-DZ-tFNA also enables image-guided surgical excision in vivo and effective monitoring of drug resistance in NB. In summary, UUU-DZ-tFNA enables in situ detection of UDG, facilitating risk stratification and drug resistance monitoring of NB.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by poor prognosis because of a lack of effective therapeutic agents. Changes in extracellular matrix (ECM) composition, particularly type I collagen density, significantly influence crucial cellular activities. However, the association between type I collagen density and TNBC progression remains unclear. This study finds that type I collagen density and mechanical characteristics of lesions predict the pathological grade and malignant progression of TNBC patients. The results of transcriptomics and metabolomics studies suggest that high-density type I collagen promotes TNBC ferroptosis. Further in vitro experiments indicate that high-density type I collagen promotes ferroptosis in TNBC cells through spermidine/spermine N1-acetyltransferase 1 (SAT1)/argininosuccinate synthase (ASS1)-induced glutamine (Gln) accumulation. Moreover, in vitro co-culture and in vivo experiments reveal that high-density type I collagen increases the uptake of Gln in TNBC cells, leading to Gln deprivation of IFN-γ CD8 T cells in the tumor microenvironment, resulting in higher level of immunosuppression. Combination of ferrostatin 1 and anti-PD-1 therapy reverses high-density collagen-induced tumor progression of TNBC. The clinical samples further verify the role of collagen density in TNBC. This study reveals that high-density type I collagen participates in TNBC progression partly through immunosuppression induced by Gln accumulation-related ferroptosis.

CD8T cells are central mediators of antitumor immunity, and their functional heterogeneity profoundly influences immunotherapy efficacy. We characterized the spatial distribution of CD8T cell subsets stratified by PD-1 expression within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). Our analyses revealed that PD-1CD8T cells were more prevalent in the non-central regions than in the tumor core, and higher abundance of these cells in the non-central zone was associated with poorer response to PD-1 blockade. Enrichment of PD-1CD8T cells diminished cancer cell apoptosis induced by anti-PD-1 mAb treatment in an in vitro co-culture system modeling in vivo conditions. The PD-1CD8T cell subset exhibited significantly reduced clonal diversity, as determined by TCR Vβ repertoire analysis, single-cell T cell receptor sequencing (scTCR-seq), and GLIPH2 clustering, along with impaired effector functions and distinct transcriptional programming. Mechanistically, IL-6 produced dominantly by non-central tumoral BTLAB cells promoted PD-1 expression on CD8T cells, mirroring the spatial pattern in tumoral PD-1CD8T cells. Our data further identify a spatially organized functional unit comprising PD-1CD8T cells and neighboring BTLAB cells within the non-central tumor region. This specialized niche, defined by anatomical localization, functional state, TCR repertoire, and intercellular crosstalk, contributes to the establishment of resistance to immune checkpoint blockade.

Therapeutic strategies for glioblastoma have progressed considerably over recent decades. Despite the development of new biomedical technologies and advances in our understanding of physiology and disease progression, effective drug delivery to brain cancer remains a significant challenge. The challenge is delivering therapeutics to the correct location without losing therapeutics to non-desirable cells as well as overcoming the low permeability posed by the blood-brain barrier. This could be tackled by conjugating a specific targeting agent to the therapeutic or drug delivery system to guide, such as an aptamer. Aptamers are short, single-stranded oligonucleotides with high selectivity and specificity for their targets, making them primed for a vast array of diagnostic and therapeutic applications. Aptamers are powerful molecular tools with the potential to overcome many of the challenges inherent in treating brain-based diseases. Here is discussed the use of aptamers, specifically as drug delivery vehicles, for the treatment of glioblastoma. There are a multitude of drug delivery aptamers in development, each with their own optimized formulation and drug delivery strategy. This review systematically and comprehensively details every drug delivery system that includes aptamers as a glioblastoma therapy that has been published to date.

Prostate cancer (PCa) is a major cause of cancer-related death among American men. While androgen deprivation therapy (ADT) is commonly used in the treatment of rising prostate-specific antigen (PSA) levels after primary therapy, its adverse systemic side effects support exploring low-impact treatment options during the observation period of nonmetastatic PSA-only progression. Grape seed extract (GSE) is a nontoxic phytochemical that has shown anti-PCa efficacy in preclinical studies. Herein, we report the results of a completed Phase II clinical trial (CT.gov-NCT03087903) which investigated the effect of GSE in patients with PSA-only recurrence after maximum local therapy for PCa. Study endpoints included PSA response (defined as a ≥ 30% increase in model-estimated PSA-DT) and change in PSA velocity. Forty-one patients were given 150 mg of GSE orally twice daily (Leucoselect-Phytosome formulation with increased bioavailability) for 12 months or until PSA-DT ≤ 3 months. Mixed-effects spline modeling of longitudinal PSA demonstrated a modest increase in PSA-DT following treatment initiation. Most patients experienced some degree of increase in model-estimated PSA-DT, with 37% of those patients meeting the primary endpoint of ≥ 30% increase in PSA-DT. GSE demonstrated a favorable safety profile. Although further validation is warranted, the observed changes in PSA-DT indicate that GSE may contribute to delaying PCa progression. The therapeutic effect appeared to be more pronounced among patients with higher baseline PSA and testosterone levels, suggesting that these factors may influence responsiveness to treatment. These promising findings support further investigation to identify patient populations most likely to benefit from GSE intervention. Trial Registration: ClinicalTrials.gov site (CT.gov-NCT03087903).

Ductal carcinoma in situ (DCIS) is a non-invasive precursor of invasive ductal carcinoma (IDC), yet the biological mechanisms underlying the transition from DCIS to IDC remain incompletely understood. Here, we integrate spatial transcriptomics, single-cell RNA sequencing, and single-cell DNA sequencing on coexisting DCIS and IDC samples to characterize cellular and microenvironmental alterations. Integrated analyses reveal differential molecular characterizations between coexisting DCIS and IDC and identify candidate genes (MGP, PLAT, and SERPINA3) potentially limiting the progression from DCIS to IDC. Malignant epithelial meta-programs (MPs) delineate distinct transcriptional states, with development-associated MP1 enriched in DCIS and cell cycle-related MP5 enriched in IDC. Further analysis reveals varied microenvironmental features in DCIS and IDC, with invasion-associated Mph_SPP1 and development-associated iCAFs_HOPX enriched in DCIS, while immunosuppressive Mph_PRDM1 and metabolism-related tCAFs_BNIP3 predominate in IDC. We then construct a machine learning model to identify DCIS at high risk of progression, which is externally validated across independent bulk RNA-sequencing cohorts (mean AUC = 0.903). Collectively, this study provides an integrative framework for understanding the molecular and spatial features that distinguish DCIS from IDC, with the potential to inform more precise risk stratification and clinical management for DCIS progression.

Acquired resistance to temozolomide (TMZ) remains a major therapeutic challenge in glioblastoma (GBM), with metabolic reprogramming emerging as a critical driver of treatment failure. Procollagen lysyl hydroxylase 1 (PLOD1) is identified as a key regulator of adaptive metabolic remodeling in TMZ-resistant GBM. Elevated PLOD1 promotes a hyper-glycolytic phenotype by maintaining the stability of the glycolytic enzyme alpha-enolase (ENO1). Mechanistically, PLOD1 catalytic activity increases an ENO1-associated hydroxylation signal, promotes ENO1 stability, and limits FBXW7-dependent ubiquitination and proteasomal degradation. Structural and functional analyses reveal that the central Ndst region of PLOD1 mediates substrate interaction, whereas its catalytic domain is required for ENO1 stabilization and downstream metabolic regulation. Clinically, PLOD1 and ENO1 expression levels are positively correlated in GBM specimens, and their co-expression is associated with unfavorable patient outcomes. In xenograft models, inhibition of the PLOD1-ENO1 axis suppresses tumor progression and enhances TMZ responsiveness. These findings establish the PLOD1-FBXW7-ENO1 regulatory axis as a critical mediator of GBM metabolic adaptation and therapeutic resistance, highlighting its potential as a prognostic biomarker and therapeutic target.

Iron homeostasis plays a critical role in the pathogenesis and therapeutic management of hepatocellular carcinoma (HCC). Magnetoreceptor (MagR), also known as iron-sulfur cluster assembly protein 1 (ISCA1), is a conserved protein maintaining iron homeostasis, plays an undefined role in HCC. The present study aimed to elucidate MagR's functional involvement in HCC pathogenesis and sorafenib-induced ferroptosis, and to explore its therapeutic potential for HCC. Pan-cancer analyses showed that MagR was significantly upregulated in HCC tissues compared with normal liver tissues, accompanied with advanced stage and poor prognosis in patients. Functional experiments further demonstrated that MagR deficiency suppressed HCC cell proliferation, migration, and invasion while enhancing the sensitivity of these cells to sorafenib-induced ferroptosis, whereas overexpression of MagR had opposite effects. Mechanistically, MagR promoted HCC progression by sustaining cellular iron homeostasis and preserving mitochondrial function, and mediated ferroptosis sensitivity of HCC cells via regulating intracellular iron accumulation. Notably, in vivo studies showed that MagR ablation not only attenuated the growth of HCC xenograft tumors but also potentiated the antitumor efficacy of sorafenib. Collectively, these findings identify MagR as a potential therapeutic target for HCC and establish that therapeutic strategies targeting MagR could optimize sorafenib-based treatment regimens for this disease.

Stimulus-responsive nanomedicines promise controlled therapy, yet most systems rely on passive delivery and lack precise, externally programmable activation while maintaining clinical compatibility. Here we engineer sub-200 nm, perfluorocarbon (PFC)-core nanodroplets (ND) that integrate efficient drug loading, physiological stability, and acoustically programmable activation within a nanoscale agent. These NDs are fabricated using microfluidic nanoassembly to achieve controlled size and composition, and are designed to encapsulate fluorinated payloads within the liquid core. Upon exposure to sequential dual-frequency ultrasound (US), the NDs undergo acoustic droplet vaporization followed by low-frequency cavitation, enabling spatially confined disruption and on-demand payload release within clinically relevant acoustic limits. These properties are engineered to overcome physicochemical barriers in solid tumors, including dense extracellular matrix and restricted drug penetration. This approach achieves enhanced payload release and induces mechanochemical cytotoxicity in vitro. In vivo, NDs exhibit prolonged circulation and tumor accumulation, while US activation drives tissue fractionation, controls drug release, and increases subsequent nanoparticle uptake. When applied to a solid tumor model, this combined mechanochemical strategy improves tumor control and extends survival compared to either modality alone. These acoustically activatable NDs provide a versatile system for stimulus-responsive, site-targeted drug delivery and tumor disruption, with strong potential for clinical translation.

Elevated copper levels are associated with chronic obstructive pulmonary disease (COPD) and susceptibility to acute exacerbations of COPD (AECOPD), but the underlying mechanisms remain unclear. This study aimed to investigate the association between copper levels and AECOPD and elucidate the underlying mechanisms. A cross-sectional analysis of NHANES 2011-2012, a hospital-based case-control study enrolling 30 AECOPD patients and 30 healthy controls, and a one-year prospective follow-up of COPD patients demonstrated that higher serum copper levels were associated with more frequent exacerbations and earlier recurrence. Integrated studies using copper-manipulated COPD mice, zebrafish, lung organoids, and BEAS-2B cells, together with bulk and single-cell RNA sequencing, colorimetric copper quantification, ELISA-based tumor necrosis factor-α (TNF-α) measurement, oxidative stress and mitochondrial functional analyses, and FITC-dextran permeability assays, showed that excess copper induced mitochondrial oxidative stress, tight-junction loss, and epithelial barrier dysfunction. Mechanistic analyses revealed that TNF-α suppressed ATPase copper-transporting alpha (ATP7A) transcription through competition between NF-κB and CREB1 for the shared coactivator CBP, thereby promoting intracellular copper accumulation. ATP7A restoration alleviated epithelial injury, whereas ATP7A silencing abolished the improvement conferred by anti-TNF-α therapy in COPD mice. These findings identify the copper-TNF-α/ATP7A axis as a mechanism underlying AECOPD and a potential therapeutic target.

Plant-derived nanovesicles have emerged as promising natural nanotherapeutics for cancer treatment, yet whether they can overcome the intrinsic resistance of tumor cells to cytotoxic T-cell-mediated killing remains largely unexplored. Here, we show that lipid-enriched Platycodon grandiflorus-derived nanovesicles (PGNs) sensitize gastric cancer to immune attack through ferroptosis-driven plasma membrane mechanical remodeling. Mechanistically, PGNs reprogram tumor lipid composition by coordinately suppressing the SLC7A11-GPX4 antioxidant axis while delivering polyunsaturated fatty acids, particularly Gamma-linolenic acid, thereby promoting glutathione depletion, lipid peroxidation, and ferroptosis. Transcriptomic analyses further revealed coordinated attenuation of malignant epithelial programs together with remodeling of membrane-associated and glutathione metabolic pathways following PGN treatment. Fluorescence lifetime imaging microscopy and atomic force microscopy revealed concomitant increases in plasma membrane tension and cellular stiffness during ferroptosis, facilitating perforin pore formation and enhancing the susceptibility of gastric cancer cells to cytotoxic T-cell-mediated killing. Collectively, these findings establish a mechanistic link between ferroptosis-driven membrane mechanical remodeling and tumor immune susceptibility, highlighting plant-derived lipid nanovesicles as a promising natural strategy for enhancing antitumor immunity.