Metabolic syndrome (MetS) is a recognized risk factor for prostate cancer (PCa), yet the precise biological mechanisms driving this association remain poorly understood. Unraveling these molecular pathways is essential for developing targeted interventions to improve patient outcomes. In this study, we analyzed NHANES (2005-2014) data to examine associations between MetS and PCa outcomes, finding that MetS was significantly associated with higher PCa risk (OR = 1.52), all-cause mortality (HR = 1.53), and cancer-specific mortality (HR = 2.17). Through integrated multi-omics, weighted gene co-expression network analysis, and machine learning, we identified the orphan receptor GPRC5B as a critical hub gene downregulated in both conditions. Single-cell transcriptomic analysis further confirmed that GPRC5B is predominantly expressed in endothelial cells. Mechanistically, GPRC5B loss was found to hyperactivate p38 MAPK signaling through a specific dual mechanism: increasing phosphorylation of upstream MKK3/6 kinases while concurrently suppressing the negative feedback phosphatase DUSP1. This synergistic dysregulation drove enhanced endothelial proliferation, migration, and tube formation in vitro. In vivo, endothelial GPRC5B deficiency significantly accelerated tumor growth and neovascularization, phenotypes that were effectively reversed by the p38 inhibitor SB202190. Clinical specimens corroborated reduced GPRC5B expression and increased microvessel density in MetS-associated PCa. Collectively, our findings establish endothelial GPRC5B downregulation as a key molecular driver promoting pathological angiogenesis via the MKK3/6-DUSP1-p38 axis, suggesting that targeting this signaling cascade offers a promising therapeutic strategy for managing MetS-associated PCa aggression.

ABSTRACT Antibody–drug conjugates (ADCs) have emerged as a major therapeutic modality in oncology, enabling the targeted delivery of highly potent cytotoxic agents while expanding the therapeutic window in solid tumors. Recent clinical successes across breast, lung, and genitourinary cancers have highlighted that ADC efficacy is governed not only by target expression, but also by the integrated optimization of antibody engineering, linker chemistry, payload selection, and tumor‐specific biology. In this review, we summarize the fundamental principles underpinning ADC design, including antibody format and Fc engineering, linker stability, payload classes, drug‐to‐antibody ratio optimization, and the bystander effect. We then discuss tumor antigen biology and target landscapes across solid tumors, with particular emphasis on how antigen density, heterogeneity, internalization kinetics, and intracellular trafficking shape clinical activity. Uro‐oncological malignancies—especially urothelial carcinoma—are presented as a clinically advanced and instructive paradigm for ADC development. Experience from these tumors illustrates both the opportunities and limitations of ADC therapy, including mechanisms of response and resistance, biomarker‐driven patient selection, rational combination strategies, and safety management in real‐world practice. Finally, we provide a forward‐looking perspective on next‐generation ADC development, highlighting emerging conjugation technologies, bispecific and conditionally activated ADCs, strategies to overcome resistance, and evolving clinical trial designs. By integrating engineering principles with tumor biology and clinical execution, this review aims to offer a translational framework to guide the future development and implementation of ADCs across oncology.

Prostate cancer (PCa) is characterized by significant metabolic heterogeneity, particularly in glutathione (GSH) metabolism. Elevated GSH metabolism is closely linked to PCa progression, therapeutic resistance, and poor clinical outcomes. Recent studies have highlighted the impact of protein butyrylation on cancer biology, although related therapeutic strategies remain limited. Herein, we utilized a cysteine-based, GSH-responsive polymer (Cys8E) to deliver a broad-spectrum antitumor agent CBL0137. Exploiting high GSH levels in PCa cells, the resulting CBL0137-loaded nanoparticles (Cys8E@CBL NPs) achieved targeted and efficient intracellular delivery and enhanced tumor-killing efficacy. Mechanistic investigations revealed that upon internalization by tumor cells, Cys8E NPs perturbed butyrate-associated metabolic homeostasis, as reflected by altered abundance of related metabolic enzymes and increased intracellular protein butyrylation levels. This metabolic remodeling was accompanied by enhanced lysine-95 butyrylation of PGAM5, which promoted necroptosis. Collectively, these findings define Cys8E@CBL NPs as a redox-responsive formulation in which the carrier contributes to therapy not only by improving CBL0137 delivery but also by reshaping butyrate-associated metabolism. This process promotes PGAM5 K95 butyrylation and strengthens necroptotic tumor cell killing. These results extend the design rationale of nanomedicine from passive payload transport toward active regulation of metabolism-dependent post-translational signaling in prostate cancer.

Cholesterol metabolism influences prostate cancer (PCa) progression, especially by affecting the tumor microenvironment. The present study demonstrated that cancer cell-intrinsic cholesterol promoted the S-palmitoylation of specificity protein 1 (SP1), enhancing SP1 nuclear translocation and driving the transcription and secretion of midkine (MDK), which in turn facilitated the differentiation of macrophages into a lipid-associated phenotype. Furthermore, targeting cholesterol metabolism with simvastatin significantly reduced MDK levels, inhibited immunosuppressive macrophage polarization, and enhanced the efficacy of enzalutamide in vivo. These findings suggested that targeting the cancer cell-intrinsic cholesterol-induced immunosuppressive tumor microenvironment could be an effective strategy to improve therapeutic outcomes in prostate cancer patients.

Background Postprostatectomy incontinence (PPI) is a common complication after robot-assisted radical prostatectomy and significantly impairs patients’ quality of life. Although behavioral interventions such as pelvic floor muscle training and bladder diaries are evidence-based, their effectiveness is often limited by poor adherence and lack of personalization. Objective This study aimed to develop and evaluate a reinforcement learning (RL)–driven clinical behavioral intervention-supporting system (CBISs) for adaptive, personalized rehabilitation in patients with PPI. Methods The study comprised 2 sequential stages. First, the CBISs was developed through (1) construction of a medical record database from a prospective cohort of PPI patients using standardized 3-day bladder diaries, (2) design of functional modules and user interfaces based on clinical rehabilitation needs, and (3) development of an RL model using XGBoost (extreme gradient boosting) and Bayesian optimization to generate individualized training plans. Second, a separate cohort of 16 patients participated in a single-arm, pre-post pilot study to evaluate feasibility and preliminary outcome trends over a 3-month intervention period, with assessments based on bladder diary parameters and system usage metrics. Results The CBISs successfully implemented an adaptive, closed-loop behavioral rehabilitation framework that dynamically tailored training recommendations according to individual voiding patterns, fluid intake behaviors, and adherence signals. Feasibility outcomes were favorable, with high system engagement observed throughout the intervention (mean usage frequency 5.2, SD 1.1 times per day). In exploratory pre-post analyses (n=16), consistent directional improvements were observed across multiple outcomes. Mean daytime urinary frequency decreased from 5.74 (SD 1.21) episodes per day to 4.69 (SD 1.08) episodes per day, while median nighttime urinary frequency declined from 1.8 (IQR 1.6-2.2) episodes per night to 1.0 (IQR 1.0-1.6) episodes per night. Median incontinence episodes were reduced from 7.0 (IQR 6.0-11.0) episodes per day to 4.0 (IQR 2.0-6.0) episodes per day. Objective urine leakage measured by the 1-hour pad test decreased from a median of 8.5 (IQR 4.0-19.0) g to 3.5 (IQR 2.0-9.0) g. Patient-reported symptom burden, assessed using the International Consultation on Incontinence Questionnaire–Short Form (ICIQ-UI SF), showed a median reduction from 14.0 (IQR 12.0-20.0) points to 9.0 (IQR 6.0-16.0) points. Although several within-participant changes were statistically detectable, effect magnitudes varied across individuals. Given the single-arm design, small sample size, and lack of a control group, findings are presented as exploratory and hypothesis-generating rather than confirmatory of clinical efficacy. Conclusions The CBISs represents the first RL-powered digital therapeutic system for PPI, enabling adaptive, evidence-based behavioral optimization. By addressing limitations of static rehabilitation protocols and declining adherence, it offers a scalable approach for personalized PPI management. Future multicenter trials are needed to confirm its clinical effectiveness.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, yet its response to immunotherapy is notably limited compared to other solid tumors. This resistance stems primarily from a highly immunosuppressive tumor microenvironment (TME), characterized by “cold” tumor features such as low mutational burden, scarce cytotoxic T cell infiltration and extensive regulatory cell populations. Building upon the “tumor ecosystem” concept, we integrate emerging insights from single-cell and spatial transcriptomics to decode the spatiotemporal heterogeneity of the PCa ecosystem. We specifically highlight the underappreciated “neural-immune-microbiome” axis—a triangular regulatory network wherein sympathetic nerves suppress T cell motility, intratumoral microbiota drive chronic inflammation, and metabolic reprogramming creates lipid-mediated immune paralysis. We further dissect how cell-type specific remodeling mechanisms, particularly TREM2+ macrophage-mediated metabolic symbiosis, drive the transition from hormone-sensitive to castration-resistant disease. Furthermore, we critically assess how standard of care (ADT, chemotherapy, radiotherapy) and emerging agents (PARPi, HDACi) reprogram the immune landscape with time-dependent, often paradoxical effects. Finally, we propose a roadmap for precision oncology, emphasizing that future success lies in “ecological editing”—biomarker-driven patient stratification and rational combination strategies to overcome the physical and biological barriers of the TME.

Resistance to second-generation antiandrogens like enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC) is a major clinical challenge, yet the role in the tumor microenvironment remains poorly understood. This study identifies a unique AR-positive tumor-associated macrophages (AR+ TAMs) subpopulation, enriched in ENZ-resistant patients and correlated with poor prognosis, which acquires functional AR protein not through endogenous expression but via ANXA2-dependent phagocytosis of tumor cells. The internalized AR protein translocates to the macrophage nucleus, directly binds the IL-6 promoter to enhance its transcription and secretion. Macrophage-derived IL-6 subsequently activates the JAK2/STAT3 pathway in cancer cells, suppressing ENZ-induced apoptosis and conferring therapeutic resistance. Genetic or pharmacological blockade of IL-6 signaling restored ENZ sensitivity in vitro and in vivo, and combining an anti-IL-6 antibody with ENZ synergistically overcomes resistance in patient-derived xenograft and orthotopic models. These findings reveal a novel phagocytosis-mediated, paracrine mechanism of ENZ resistance orchestrated by AR+ TAMs, challenging the tumor-centric view of therapy failure and providing a strong rationale for co-targeting the IL-6 pathway to improve outcomes of AR-directed therapy in CRPC.

Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating cuproptosis, offering a promising therapeutic approach for treating refractory prostate cancer.