HOX code-based stratification reveals RUNX1T1-HDAC reprogramming as a targetable driver of lineage plasticity across cancers.

Dual-targeting nuclear and mitochondrial DNA damage drives immunogenic activation via PANoptosis for synergistic magneto-thermodynamic-chemotherapy.

A MICA/B GAALIE-mutant antibody elicits potent natural killer cell-driven immunity in solid and hematologic malignancy models.

Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.

This study aimed to explore the association between caffeine intake, physical activity (PA), and prostate cancer, machine learning algorithms to build predictive models of prostate cancer. A total of 1789 subjects from the National Health and Nutrition Examination Survey 2009 to 2018 waves were enrolled in this study. Multivariable-adjusted logistic regression was applied to evaluate the association. Then, we conducted 4 machine learning models, including extreme gradient boosting, AdaBoost, Catboos, and Boost tree to predict the occurrence of prostate cancer. In the fully adjusted model, compared to those reporting little caffeine consumption, those who reported large intake had a multivariate adjusted odd ratio (OR) with 95% confidence interval (CI) of 1.25 (2.21–15.52). Participants with large PA were more likely to develop prostate cancer (OR = 1.68, 95% CI: 1.47–3.80), whereas a significant inverse association between medium PA and prostate cancer was observed (OR = 0.66, 95% CI: 0.48–0.81). Extreme gradient boosting, Catboost, and Boost tree all have good prediction effects, with an AUC of up to 0.90 (95% CI: 0.87–0.93). No significant association was observed between small to medium caffeine intake and prostate cancer, large caffeine intake and PA was associated with increased prostate cancer. Moderate PA has the potential to favorably influence prostate cancer.

The localization of prostate cancer by ultrasound remains limited by the lack of B-mode conspicuity and the confinement of clinically approved microbubbles (MBs) to the vasculature. This precludes the differentiation of viable tumor tissue, necrotic tissue, and margin-associated disease. We investigate the use of prostate-specific membrane antigen (PSMA)-targeted lipid-shelled perfluorocarbon nanobubbles (PSMA-NBs) in an orthotopic rabbit model using a clinical CEUS system. We implanted PSMA-positive PC3pip-GFP tumors into the prostates of immunosuppressed New Zealand White rabbits and performed transabdominal imaging with PSMA-NBs, MBs, and untargeted nanobubbles (Plain-NB) using the same imaging and analysis protocols. To address tumor heterogeneity and ultrasound boundary ambiguity, ROIs were defined from baseline B-mode images and segmented into the tumor core, rim, and a surrounding peritumoral area. Pixel-wise parametric and decorrelation time (DT) maps were generated and correlated with whole-slide histology (H&E) and PSMA IHC. Compared to MBs, PSMA-NBs exhibited higher peak intensities in the tumor core and rim (1.60-fold and 1.50-fold, respectively) and improved retention (mean transit time: 4.20 to 4.50-fold higher) for up to 10 minutes in the tumor and peritumoral areas. PSMA-NB kinetic and DT parameters also correlated with histology-defined tumor viability and PSMA expression. Compared to Plain-NBs, PSMA-NBs also exhibited improved retention (MTT +21%; AUCwo) in the rim and peritumoral areas. This study demonstrates the capability of PSMA-NBs to characterize prostate cancer by molecular CEUS beyond what is possible with conventional MBs.

Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53 -deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a's anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53 -deficient cells fail to detect DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a's efficacy in TP53 -deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.

Prostate-specific membrane antigen (PSMA)-based vaccination represents a promising immunotherapeutic strategy for prostate cancer; however, its efficacy remains constrained by tumor-induced immune evasion and insufficient activation of antigen-presenting cells. Galectin-9 (LGALS9), an immunoregulatory lectin that contributes to immune suppression, is therefore an attractive target for overcoming tumor-induced immune tolerance. Recombinant adenoviral vaccines encoding PSMA and LGALS9 (Ad-PSMA and Ad-LGALS9) were generated and validated for antigen expression in vitro and in vivo. Therapeutic efficacy was evaluated in murine subcutaneous, bone metastatic, and humanized prostate cancer models. Vaccine-induced immune responses were characterized by flow cytometry, ELISA, enzyme-linked immunospot (ELISpot), immunohistochemistry, EdU proliferation assays, cytotoxic T lymphocyte assays, and cell depletion experiments. Pre-immunization with Ad-LGALS9 significantly potentiated the therapeutic efficacy of the Ad-PSMA vaccine in subcutaneous, bone metastatic, and humanized prostate cancer models, resulting in pronounced tumor growth inhibition and prolonged survival. Mechanistically, LGALS9 targeting enhanced dendritic cell (DC) activation and maturation, upregulating CD80, CD86, major histocompatibility complex-II, and CD40 expression and promoting efficient antigen cross-presentation. This facilitated robust priming and expansion of multifunctional CD8+ T cells producing interferon-γ, interleukin-2, and tumor necrosis factor-α, which mediated potent cytotoxicity against PSMA-expressing tumor cells. Furthermore, LGALS9 immunization induced high-titer neutralizing antibodies that disrupted the LGALS9/TIM-3 inhibitory axis, alleviating T-cell exhaustion. Combined Ad-LGALS9/PSMA vaccination established durable memory CD8+ T-cell responses that conferred protection against tumor rechallenge. Targeting LGALS9 enhances DC-mediated CD8+ T-cell immunity and synergistically augments the therapeutic efficacy of tumor vaccines, representing a promising immunotherapeutic strategy for prostate cancer.

Prostate cancer continues to represent a significant global health burden with androgen deprivation therapy (ADT) serving as the cornerstone of systemic management. Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist has demonstrated rapid and sustained testosterone suppression compared with conventional ADT agents such as degarelix, which are primarily available as depot-based injectable formulations and are associated with delayed absorption, limited dose flexibility, and injection-site reactions. However, the clinical utility of relugolix is constrained by its low oral bioavailability (~ 12%), attributable to incomplete absorption and extensive first-pass metabolism. In this study, we developed and evaluated a citrate-buffered injectable formulation of relugolix to overcome these limitations. Pharmacokinetic assessment in a preclinical prostate cancer model revealed that intravenous administration achieved significantly higher systemic exposure compared to oral dosing, with a peak plasma concentration of ~ 4300 ng mL-1 at 5min versus ~ 427 ng mL-1 at 3h, corresponding to an approximately nine-fold increase in area under the curve (AUC). Enhanced systemic availability resulted in greater early-phase tumor drug accumulation. Therapeutic efficacy was evaluated in the Myc-CaP allograft model, where the injectable formulation demonstrated significantly improved tumor growth inhibition compared to oral administration. Safety evaluation indicated good tolerability, with no significant alterations in hematological, biochemical, or urinalysis parameters. Collectively, these findings demonstrate that parenteral delivery substantially enhances the pharmacokinetic and therapeutic performance of relugolix, supporting further translational development of injectable formulations for improved prostate cancer management.

Clinical utility of large language models in metastatic prostate cancer: A multicenter expert validation for decision support.

Vitamin E and related tocols in cancer: Unraveling the paradox of antioxidant and pro-oxidant roles.

BCL-2 has been implicated in prostate cancer (PCa) progression and development of castration-resistant disease (CRPC); however, it remains unclear how the BCL-2- and AR-expressing PCa cell populations evolve across the PCa continuum, how AR molecularly regulates BCL-2 and whether BCL-2 represents a common therapeutic target in heterogeneous CRPC. Here we first show the selective induction of BCL-2 by AR pathway inhibitors (ARPIs). Vectra-based quantitative multiplex immunofluorescence (qmIF) and image mass cytometry (IMC) analyses with single-cell resolution in patient PCa and xenograft models reveal markedly increased BCL-2+ (AR+ or AR-) PCa cells in CRPC. Mechanistically, AR represses BCL-2 transcription through several AR binding sites and ARPIs relieve this repression. Therapeutic studies in cells, organoids and xenografts support BCL-2 as a shared vulnerability across diverse CRPC subtypes. A Phase Ib clinical trial (NCT03751436) combining enzalutamide and BCL-2 inhibitor venetoclax demonstrated reduced circulating tumor cells in responding patients. In summary, by integrating high-content single-cell level imaging analyses with mechanistic studies, extensive preclinical therapeutic experiments and a Phase Ib clinical trial, our studies herein elucidate the AR+/-BCL-2+/- PCa cell subpopulation dynamics and credentials BCL-2 as a vital therapeutic target in heterogeneous CRPC.

Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PI3K inhibition may enhance anti-tumor immune activity. RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS-STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile. The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p<0.006). Triple therapy with the PIM kinase inhibitor PIM447, anti-PD-1, and RT nearly tripled the median survival compared to PIM447 monotherapy (82 days vs 29 days, p=0.002). Mass cytometry analysis revealed that the combination of anti-PD-1 and RT reduced myeloid-derived suppressor cells and tissue-associated macrophages and enhanced CD8+ T-cell infiltration. Although prostate cancer is an immunocold entity, RT can trigger immune activation, consistent with engagement of the cGAS-STING signaling pathway (cytosolic dsDNA serving as a surrogate upstream marker). In triple therapy, RT can enhance the efficacy of ICI and PI3K-targeted drug therapy, significantly improving overall survival in a mouse model of CRPC. A combination of RT, ICIs, and PIM kinase inhibition may help overcome immune resistance in prostate cancer. This combination therapy approach supports further preclinical validation and careful clinical evaluation and warrants further clinical investigation to optimize treatment strategies for CRPC.

Lactoferrin (LF), an iron-binding glycoprotein, has recently emerged as a multifunctional potential nanocarrier for tumor-targeted drug delivery applications. Based on its ability to bind with high affinity to receptors overexpressed by cancer cells, LF enables receptor-mediated endocytosis and selective drug delivery to tumor tissues. A wide range of LF-based nanocarriers have been developed including LF nanoparticles (NPs), LF-drug nanoconjugates, LF-coated nanocarriers, LF-inorganic nanohybrids, LF nanogels, and LF-drug noncovalent nano-assemblies. These nanocarriers have shown improved tumor accumulation, enhanced antitumor efficacy, and decreased side effects in preclinical models of brain, prostate, breast, colorectal, and lung cancers. Although clinical translation is still in its early stages, recombinant human LF exhibited favorable pharmacokinetics and excellent safety profile in clinical trials. Future progress will require enhancing nanoparticle stability, limiting off-target biodistribution, and refining targeting strategies to account for heterogeneous receptor expression across tumors. Among promising future directions, engineering ultrasmall recombinant LF-based nanocarriers capable of penetrating dense tumor stroma holds potential applications in the treatment of desmoplastic tumors. Overall, LF-based nanocarriers offer a versatile platform for safe, receptor-mediated targeted cancer therapy.

Co-activating the intrinsic FcRγ/TLR4 signaling axis enhances the antitumor activity of NKG2D CAR-macrophages against prostate cancer.

Fluorescence-guided surgery (FGS) offers a potential strategy to improve complete tumor resection in prostate cancer (PCa); however, clinical application has been limited by an insufficient tumor-to-background ratio (TBR) of available probes. Here, we report the development of GGA-sNIR, a near-infrared (NIR) fluorescent probe engineered by conjugating a high-affinity DNA aptamer specific for a prostate stem cell antigen (PSCA) with a monocarboxy indocyanine green (ICG) derivative. The conjugate adopts a stable three-dimensional structure that not only enables precise target recognition but also protects against nuclease degradation, markedly enhancing its in vivo stability. GGA-sNIR exhibits nanomolar binding affinity (Kd = 54.91 nM) and is specifically internalized by PSCA-positive cells. In subcutaneous tumor models, the probe achieved a peak TBR of 26 and showed prolonged tumor retention exceeding 48 h. Crucially, in an orthotopic PCa model, GGA-sNIR allowed real-time, high-contrast visualization of tumor margins during laparoscopic surgery, facilitating precise and complete resection. Further validation using ex vivo human lymph node specimens confirmed its ability to selectively detect PSCA-positive metastases. With its ultrahigh contrast, demonstrated efficacy in intraoperative guidance, and strong translational potential, GGA-sNIR represents a promising molecular tool for advancing precision surgery in prostate cancer.

Construction of an integrated diagnostic-therapeutic model for prostate cancer using rapid multiplex immunohistochemistry.

Castration-resistant prostate cancer (CRPC) exhibits an immunologically "cold" tumor microenvironment (TME) dominated by M2 tumor-associated macrophages (TAMs), limiting cytotoxic immune infiltration and promoting tumor progression. Targeting M2 macrophages may represent a promising therapeutic strategy. TB511 was synthesized by conjugating a TAM-specific peptide (TAMpep) to a pro-apoptotic d-form KLA peptide via a GGGGS linker. Its structure was characterized by FTIR and CD spectroscopy. Binding affinity to CD18 was determined by biolayer interferometry. A humanized prostate cancer model was established by subcutaneous implantation of PC-3 cells into hCD34+-reconstituted immunodeficient mice. TB511 exhibited high binding affinity to CD18 (KD < 5 nM), selectively induced apoptosis in M2 macrophages, and co-localized with mitochondria. In vitro, TB511 reduced macrophage viability, suppressed tumor spheroid growth, and inhibited Ki-67 and vimentin expression. In both syngeneic and humanized models, TB511 reduced tumor burden, increased M1/M2 ratio, and downregulated EMT/angiogenesis/proliferation markers. It also decreased CD8⁺ T cell exhaustion and enhanced cytotoxic CD8⁺ and NK cell activation. In vivo imaging confirmed tumor-specific accumulation and co-localization with CD206⁺/CD18⁺ cells. Collectively, CD18-targeted depletion of M2 macrophages effectively reprogrammed the immunosuppressive TME of prostate cancer, restored anti-tumor immunity, and suppressed tumor progression, supporting peptide-drug conjugates targeting M2 TAMs as potential immunotherapeutics for CRPC.

Cancer remains a leading cause of morbidity and mortality globally, with current therapies often limited by toxicity, drug resistance, and reduced efficacy in advanced stages. Medicinal plants represent important sources of bioactive compounds (BACs) with anticancer and chemopreventive potential; however, their successful application is strongly influenced by extraction strategies that determine phytochemical recovery and downstream biological activity. This review evaluates solvent-based extraction techniques used to extract BACs from medicinal plants with reported anticancer properties, synthesizing peer-reviewed articles from PubMed and Google Scholar published between 2020 and 2025. Solvent-based methods, including Soxhlet and maceration, were most widely applied due to their operational simplicity and the preservation of structurally diverse metabolites while percolation, decoction, infusion, and hydro-distillation were sparsely utilized. Extraction strategy and solvent polarity emerged as primary factors shaping phytochemical profiles, with phenolics, flavonoids, alkaloids, and terpenoids identified as dominant classes. Reported half maximal inhibitory concentration (IC50) ranged from highly potent (0.12 µg/mL) to weak (30,000 µg/mL), reflecting variability driven by extraction parameters and plant matrix complexity. Anticancer mechanisms commonly involved apoptosis induction, cell-cycle arrest, reactive oxygen species-mediated cytotoxicity, and inhibition of proliferative signaling pathways across breast, cervical, colon, lung, liver, and prostate cancer models. Although solvent-based extraction approaches remain widely used, their context-dependent nature and lack of standardization limit reproducibility. Overall, anticancer and chemotherapeutic efficacy is primarily governed by BAC composition, while extraction methods act as upstream modulators. Future progress requires phytochemical-informed, standardized workflows supported by hybrid extraction systems, AI-assisted optimization, and advanced bioavailability and delivery systems to enable reproducible and clinically relevant translation of plant-derived chemotherapeutics.

Prostate cancer remains the second most common cancer among men around the world, with 1.4 million new cases annually. Treatment resistance and off-target toxicity require innovative therapeutic approaches. Natural compounds such as eugenol exhibit anticancer potential, but poor pharmacokinetic properties constrain clinical application. This study evaluated the cytotoxic, apoptotic, and pharmacokinetic properties of three eugenolderived allyl phenol compounds (38, 42, 47), previously recognized as potent 15-lipoxygenase-1 (15-LOX-1) inhibitors, in prostate cancer models. The cytotoxic activity was evaluated in PC-3 prostate cancer cells and Human Dermal Fibroblasts (HDF) using AlamarBlue assays, flow cytometry, and morphological analysis. Computational validation involved Density Functional Theory (DFT) calculations, molecular docking into 15-lipoxygenase-1 (15-LOX-1; PDB: 2P0M), and structural analysis. Pharmacokinetic and toxicity profiles were predicted in silico using SwissADME, pkCSM, and ProTox-III platforms. All three compounds were cytotoxic to PC-3 cells in a concentration-dependent way with some selectivity for normal cells. Apoptosis was confirmed by increased sub-G1 peak and morphological changes, while BAX or BCL-2 mRNA levels did not change. In silico studies (DFT and docking) showed that the compounds bound well to 15-LOX-1 (docking scores: -6.6 to -7.3 kcal/mol), with compound 42 having the strongest binding affinity. Structural analysis showed that the proteins were moderately flexible (B-factor: 47.45 ± 13.07 Ų), which supports stable ligand accommodation. Computational ADME/toxicity predictions suggested generally favorable pharmacokinetic profiles; however, compound 42 was poorly soluble, and compound 47 was identified as a P-gp substrate, indicating a potential efflux liability. The pro-apoptotic effects observed despite unaltered BAX and BCL-2 mRNA levels indicate that the apoptotic response is likely mediated through mechanisms other than transcriptional regulation of these genes, potentially by blocking 15-LOX-1. Computational modeling indicated that all three compounds can effectively bind to the 15-LOX-1 active site, and their binding affinities are in line with their experimental inhibitory potencies (IC50: 0.80-0.88 μM). The integration of in vitro and in silico results confirms the therapeutic potential of these compounds and underscores the necessity for additional mechanistic studies and in vivo evaluation. These results highlight the anticancer properties of eugenol-derived allylphenol compounds. The compounds induce apoptosis by mechanisms independent of BAX/BCL-2 transcriptional modulation. Computational modeling suggests potential involvement of 15-LOX-1; nevertheless, direct mechanistic validation via caspase activity, ROS generation, or protein-level quantification of BAX/BCL-2 is necessary to verify the apoptotic pathway. The compounds suggest favorable pharmacokinetic profiles along with strong enzyme binding characteristics. Compound 38 exhibited the most balanced profile, characterized by high cytotoxicity, selectivity, and predicted ADME properties. Additional mechanistic investigations and in vivo validation are necessary to advance these candidates through preclinical development.