ObjectiveAdvanced prostate cancer (PCa) remains therapeutically challenging due to heterogeneous mechanisms of resistance to androgen receptor (AR)-targeting agents. While AR signaling persists in castration-resistant PCa (CRPC), emerging evidence suggests AR-independent survival pathways may contribute to therapeutic escape. This study integrates transcriptomic data and clinical profiling to dissect AR dependency and resistance mechanisms in PCa, aiming to identify subtype-specific vulnerabilities and therapeutic targets.MethodsWe performed CRISPR-Cas9 screens in AR-dependent (VCaP, LNCaP, 22Rv1) and AR-independent (DU145, PC-3, WPE1-NA22, P4E6, Shmac5) cell lines to identify core essential genes. RNA sequencing data from TCGA-PRAD, Changhai, and DKFZ cohorts were integrated to define molecular subtypes using consensus clustering. Spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) were employed to validate gene expression patterns in primary tumors and metastatic samples. Temporal expression dynamics were analyzed using fuzzy clustering to identify resistance mediators, with a focus on MCL1. Drug sensitivity analysis revealed that AR-dependent cells were more sensitive to MCL1 inhibitor UMI-77, and MCL1 expression was higher in Enzalutamide-resistant cell lines. Functional validation via MCL1 knockdown confirmed its role in supporting the proliferation and inhibiting apoptosis of resistant cells.ResultsCRISPR screening identified 952 shared essential genes in prostate cancer, with 157 AR-high essential signature and 130 AR-low essential signature genes. AR-high essential signature genes enriched in cell cycle/polycomb pathways, while AR-low essential signature genes correlated with oxidative phosphorylation/mTOR signaling. Consensus clustering of TCGA-PRAD data revealed three molecular subtypes (Clusters 1–3); Cluster 3 showed worst prognosis (shorter PFI/OS) and advanced clinical features (higher T/N stage, Gleason grade). External validation confirmed Cluster 3’s aggressive phenotype and independent prognostic value (meta-cohort HR = 1.98, 95% CI: 1.19–3.27). Cluster 3 signature genes were upregulated in metastatic/CRPC tissues and spatially enriched in CRPC epithelium. Notably, Cluster 3 shared essential gene expression decreased after Enzalutamide treatment, whereas AR-high essential signature genes remained stable. MCL1 emerged as a key resistance driver, demonstrating persistent upregulation in Enzalutamide-resistant cells and CRPC models.ConclusionsThis study elucidates distinct AR dependency landscapes in PCa, revealing AR-independent survival pathways and a clinically actionable molecular subtype (Cluster 3) linked to therapy resistance. MCL1 emerges as a critical mediator of adaptive resistance, highlighting the need for combination therapies targeting both AR-driven and AR-independent programs to improve outcomes in advanced PCa.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-15357-5.

Abstract Prostate cancer depends on androgen receptor (AR) signaling for growth, which is why androgen deprivation (castration) therapy is effective at early stages. However, many tumors eventually progress to a lethal form known as castration-resistant prostate cancer (CRPC). A subset of CRPC tumors bypass dependency on AR signaling by acquiring lineage plasticity, where prostate cancer cells transdifferentiate into alternate cellular states through epigenetic reprogramming. Neuroendocrine (NE) prostate cancer represents one well-known lineage plasticity phenotype. Nevertheless, most AR-independent tumors do not exhibit NE features and are defined as AR-negative/NE-negative or “double-negative prostate cancer” (DNPC). In a collaboration with Dr. Ekta Khurana’s computational genomics lab at Weill Cornell Medicine, we recently classified CRPC into four epigenetic subtypes, including the well-established 1) AR and 2) NE, as well as the novel DNPC subgroups 3) WNT and 4) stem cell-like (SCL) (PMID: 35617398). We focused on the SCL subtype as it is the second most common group in CRPC patients and lacks therapeutic targets. Using functional genomic approaches, we found that YAP/TAZ/TEAD cooperates with FOSL1 to drive the SCL lineage and growth of SCL models. We therefore hypothesize that the heightened dependency on the YAP/TAZ/TEAD/FOSL1 transcriptional program represents a therapeutic vulnerability in CRPC-SCL. To test this, we exposed CRPC models to TEAD inhibitors and found robust growth suppression in SCL cells compared to non-SCL cells in vitro. To evaluate whether the TEAD inhibitors are on-target, we performed transcriptomic profiling in SCL models and observed downregulation of YAP/TAZ gene signature as well as FOSL1 expression, which phenocopies the effects of YAP/TAZ double knockdown. To define the cistromes of these factors upon TEAD inhibition, we performed ChIP-seq and observed reduced co-occupancy at consensus sites, suggesting the disruption of the YAP/TAZ/TEAD/FOSL1 transcriptional circuit by the small molecule compound. To determine whether these phenotypes are recapitulated in vivo, we will treat mice harboring CRPC-SCL xenografts with TEAD inhibitors to assess growth response and evaluate epigenetic and transcriptional response using single-nucleus Multiome (ATAC+RNA). These studies will establish whether small molecule inhibition of TEAD is a promising strategy for the treatment of CRPC-SCL and allow high-resolution analysis of cell state transitions, with a focus on loss of SCL-specific signatures and potential emergence of AR/NE programs as adaptive resistance mechanisms. Citation Format: Chen Khuan Wong, Dan Li, Hongsu Wang, Marjorie Roskes, Weiling Li, Shipra Shukla, Dana Schoeps, Ekta Khurana, Yu Chen. Defining and targeting drivers of lineage plasticity in stem cell-like prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A074.

Pseudomonas aeruginosa is a predominant colonizer of airways in non-cystic fibrosis bronchiectasis (NCFB), yet its adaptive mechanisms remain poorly understood. This study investigates the genetic characteristics, virulence variation, and resistance mechanisms of 66 P. aeruginosa isolates derived from NCFB patients. Whole-genome sequencing revealed extensive genetic diversity, encompassing 53 sequence types and a predominance of the O6 serotype (30/66, 45.5%). Phylogenetic analysis indicated that most NCFB isolates were acquired independently, with limited evidence of transmission. Extensive loss-of-function mutations were identified, with mucA mutations present in 90.6% (29/32) of mucoid and 67.6% (23/34) of non-mucoid isolates. Most mucA mutations were frameshift variants, predominantly at codon 144 (Ala144fs), indicating the selective advantage of this site in driving alginate overproduction during chronic airway infection. Virulence gene profiling demonstrated a highly conserved core repertoire but considerable variability in type VI secretion and pyoverdine systems. Notably, mucoid isolates exhibited significantly higher cefiderocol MICs compared to non-mucoid isolates (P = 0.0073), along with enhanced biofilm formation (P < 0.0001) but reduced virulence in the Galleria mellonella infection model. Mechanistic studies revealed that cefiderocol resistance in mucoid P. aeruginosa was driven by synergistic interactions between alginate overproduction and mutations in iron-uptake regulatory genes, particularly Gly132 frameshift in pirR. Disruption of alginate biosynthesis (ΔalgD) and complementation of pirR in mucoid strains markedly restored cefiderocol susceptibility. These findings highlight the remarkable genomic diversity and adaptive resistance mechanisms of P. aeruginosa in NCFB, providing important insights into its persistence and therapeutic challenges in chronic airway infection.IMPORTANCEUnderstanding the adaptive mechanisms of Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis (NCFB) is critical for improving treatment strategies. This study reveals substantial genomic diversity and highlights alginate overproduction as a key feature of chronic adaptation. Notably, we uncover a novel resistance mechanism involving synergistic interactions between alginate production and mutations in iron-uptake regulators, particularly pirR. These findings underscore the complex evolutionary pressures shaping P. aeruginosa persistence in NCFB and provide valuable insights into its resistance and virulence balance, offering potential targets for more effective therapeutic interventions.

Aging is the primary risk factor for prostate cancer (PCa), characterized biologically by a systemic collapse of proteostasis networks. Paradoxically, rather than succumbing to this decline, PCa cells exploit it, developing a “proteostasis addiction” to cope with persistent intrinsic stress. This review elucidates this paradox through three conceptual frameworks: the dynamic transition from age-related functional decay to tumorigenic hijacking; the specificity of oncogenic protein regulation; and the functional dichotomy (or “double-edged sword”) of proteostatic components in tumor suppression versus promotion. We examine how declining molecular chaperone networks are co-opted to selectively stabilize the androgen receptor (AR) and its variants. Furthermore, we explore how the ubiquitin–proteasome system (UPS) is re-engineered via E3 ligases and deubiquitinases (DUBs) to orchestrate the precise turnover of tumor suppressors and oncoproteins. Special attention is given to chaperone-mediated autophagy (CMA), which undergoes a reversal from age-associated suppression to hyperactivation in advanced PCa, thereby fueling metabolic adaptation and therapy resistance. Beyond the intracellular context, we discuss how proteostatic imbalances drive the senescence-associated secretory phenotype (SASP) to remodel the tumor microenvironment. Finally, we assess emerging therapeutic strategies, arguing that precision modulation of specific proteostasis nodes—such as distinct E3/DUBs or CMA pathways—represents a promising frontier to overcome castration-resistant prostate cancer (CRPC).

Targeting PPP1R15B and ATF4 axis in hepatocellular carcinoma: A novel strategy for overcoming lenvatinib-tolerant persister cells through GPX4-mediated ferroptosis induction.

The restoration of endodontically treated teeth remains a clinical challenge, particularly when substantial coronal tissue loss is present. Endocrowns fabricated using CAD/CAM technologies offer a conservative and esthetic alternative to conventional post-core systems; however, their long-term performance may be influenced by age-related mechanical and thermal stresses. This study evaluated the effect of thermomechanical aging on the marginal adaptation and fracture resistance of endocrowns fabricated from three CAD/CAM materials: zirconia-reinforced lithium silicate (ZLS), polyetherether ketone (PEEK), and 3D-printed resin. Sixty extracted human molars were endodontically treated and restored with endocrowns produced from these materials (n = 20 per group) and then subdivided into aged (n = 10) and control (n = 10) subgroups. Thermomechanical aging involved 5000 thermal cycles between 5 °C and 55 °C, and 75,000 mechanical loading cycles at 50 N. Marginal gaps were examined using scanning electron microscopy, and fracture resistance was tested under axial load at a crosshead speed of 0.5 mm/min. Data were analyzed using two-way ANOVA followed by Tukey’s post hoc test (α = 0.05). Thermomechanical aging significantly increased the marginal gaps in all materials (p < 0.05). The smallest marginal discrepancies were observed in the 3D-printed resin group, while the largest occurred in the ZLS after aging, likely due to dimensional changes during crystallization. Fracture resistance decreased in ZLS (−21.2%) and 3D resin (−20.9%) after aging (p < 0.05) but was not significantly affected in PEEK (−5.4%, p = 0.092). Thermomechanical aging adversely affects marginal adaptation across all materials, whereas its impact on strength is material-dependent. PEEK demonstrated the most stable mechanical performance and may represent a promising alternative for long-term endocrown restorations.

Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.

Fibroblast growth factor 19 (FGF19), the human orthologue of murine FGF15, is an endocrine FGF that signals through the FGFR4-β-Klotho receptor complex to regulate bile acid synthesis, glucose and lipid metabolism, and thermogenesis. Beyond its physiological role in metabolic homeostasis, aberrant expression of FGF19 has been increasingly implicated in the initiation and progression of solid tumors. Mechanistically, FGF19 drives signaling cascades that sustain proliferation, invasion, and metabolic reprogramming, while also promoting epithelial-mesenchymal transition, angiogenesis, and immunosuppression to facilitate metastasis. These pleiotropic activities highlight FGF19 as a compelling therapeutic target, and several FGFR4-directed inhibitors have entered clinical evaluation. However, challenges remain, including on-target toxicities, limited selectivity and adaptive resistance. In this review, discuss the molecular mechanisms by which FGF19 shapes tumor biology, evaluate the current status of therapeutic strategies targeting the FGF19-FGFR4 axis, and explore future opportunities such as rational drug combinations and metabolic intervention. A deeper understanding of the interplay between FGF19 signaling, the tumor microenvironment and systemic metabolism will be essential to unlock its potential for precision oncology.

The hidden hand of endoplasmic reticulum stress in anticancer drug resistance.

The protein architecture of Mycobacterium tuberculosis (Mtb) demonstrates remarkable complexity and adaptability, emblematic of its evolutionary refinement as a highly successful pathogen. The Mtb proteome can be broadly classified into four principal categories: core, accessory, transcriptionally plastic, and uncharacterized proteins. Core proteins are highly conserved across all Mtb strains and essential for fundamental cellular functions and bacterial viability; they form the structural and metabolic foundation required for critical processes such as DNA replication, transcription, and cell wall biosynthesis. Conversely, accessory proteins exhibit considerable variability among strains, endowing Mtb with strain-specific traits including virulence, environmental adaptation, and antibiotic resistance. These proteins are vital for enabling the pathogen to thrive in diverse ecological niches and to overcome selective pressures imposed by environmental factors and antimicrobial agents. Distinguished not by strain distribution but by regulatory dynamics, transcriptionally plastic proteins exhibit differential expression in response to environmental changes and host-derived cues, allowing Mtb to modulate its physiological state during infection rapidly. This regulatory flexibility supports the pathogen's ability to enter dormancy, mount stress responses, and transition between metabolic states. A substantial portion of the Mtb proteome remains uncharacterized or annotated as hypothetical, with functions yet to be elucidated. Nevertheless, recent advances in integrative bioinformatics and experimental proteomics have begun to clarify the roles of many such proteins, revealing novel contributions to bacterial survival, pathogenicity, and immune evasion. The complex interplay among these protein categories illustrates a highly sophisticated regulatory network that governs Mtb's growth, dormancy, stress adaptation, and persistence. This dynamic and adaptable protein architecture is fundamental to the bacterium's capacity to endure hostile host environments, evade immune surveillance, and establish chronic infections. Consequently, a comprehensive understanding of the composition, regulation, and functional plasticity of these protein classes is imperative. Such knowledge will drive the development of innovative diagnostics, next-generation vaccines, and targeted therapeutics, ultimately advancing more effective strategies for tuberculosis control and eradication.

Differential roles of ABCC2, ABCC3, and cadherin in mediating Cry1Ac toxicity in Spodoptera exigua.

The central role of IL-17 in cancer stemness and immune evasion: A novel axis for overcoming immune checkpoint inhibitor resistance.

Pathogen-specific drug metabolism in tuberculosis: Enzymes, metabolic pathways, and new horizons in therapeutic development.

Haloxylon ammodendron, a keystone species forrestoring desert ecosystems, has extremely low seedling survival rates under natural conditions due to surface high-temperature and secondary drought stress. This study investigated the effects of heat priming on the tolerance of H. ammodendron seedlings to subsequent drought stress and the underlying molecular mechanisms. The results demonstrated that heat priming (37°C for 12h) significantly improved seedling survival under drought stress (simulated with 480 mmol·L⁻¹ sorbitol) and reduced cell mortality. Physiological analyses revealed that heat priming increased the activities of antioxidant enzymes (SOD, POD, and CAT) and the accumulation of proline and chlorophyll, albeit with aggravated membrane lipid peroxidation (elevated MDA content). Transcriptomic profiling revealed 909 heat-priming-specific differentially expressed genes (DEGs), which were predominantly enriched in plant‒pathogen interactions, the MAPK signaling pathway, and phenylpropanoid biosynthesis. Key genes such as WRKY24 and MAPK3 potentially mediate cross-regulation to reinforce stress memory. Furthermore, heat priming suppressed drought-induced excessive lignin accumulation, suggesting that cell wall remodeling contributes to drought tolerance. CONCLUSIONS: Collectively, heat priming activates oxidative defense, signal transduction, and metabolic reprogramming, thereby increasing cross-tolerance to secondary drought stress in H. ammodendron seedlings. These findings provide theoretical insights into its ecological adaptation and stress resistance.

Multidrug resistance (MDR) still constitutes a significant barrier to the effective treatment of lung cancer and makes a significant contribution to the poor clinical results. MDR is explained by a set of mechanisms; increase of drug efflux, metabolism, increase of DNA repair potential, inhibition of apoptotic signals, mutation or post-translational modification of drug targets. These cell intrinsic mechanisms are even aggravated by tumour-microenvironment-induced factors, epigenetics dysregulation, survival of cancer stem cells and intratumour heterogeneity, which has made resistance highly adaptive and multifactorial. In order to address this complexity emerging therapeutic strategy is dual. The former element deals with new targeted agents which are able to counter an oncogene-mediated resistance. These include next-generation tyrosine kinase inhibitors (TKIs), KRAS12C inhibitors, bispecific antibodies including ivonescimab, and they all are specific to inhibit predominant signalling cascades that promote tumoral proliferation and resistance. The second element is drug repurposing whereby it exploits already established pharmacological drugs with already a clear safety record to attack non-oncogenic vulnerabilities linked with MDR. Pharmacological modulators of autophagy including statins, disulfiram, and lysosomotropic agents (e.g., chloroquine) target metabolic vulnerabilities such as mitochondrial bioenergetics and redox homeostasis. By mitigating oxidative stress and immune evasion, these compounds act as chemo sensitizers that potentiate the efficacy of tyrosine kinase inhibitors (TKIs) and immunotherapies, effectively overcoming adaptive drug resistance. Real-time monitoring of resistance evolution can be achieved with liquid biopsies, such as circulating tumor DNA and exosomal cargo, whereas MDR-related biomarkers can be used to stratify a patient. Analytical models that are built using artificial-intelligence also guide rational combination-therapy design and the chosen selection of treatments that are personalized. Also, inhalable nano formulations and targeted drug-delivery systems optimize the bioavailability of the formulation by pulmonary determination and ameliorates the systemic toxicity. A combination of these therapeutic approaches will provide a more accurate and flexible way of conquering MDR in lung cancer.

There is a steady increase in life expectancy and in the number of elderly individuals worldwide. Aging is associated with the rise of age-related diseases and multimorbidity and therefore has become a major medical, social, and economic challenge for the state. This imposes new tasks on the healthcare system, social support services, and the state as a whole, aimed at ensuring healthy and active longevity and at developing new health-preserving technologies and strategies. Multiple pathophysiological processes underlie aging and the development of age-related diseases: oxidative stress, chronic low-grade inflammation, mitochondrial dysfunction, reduced autophagy, accumulation of damage to proteins and subcellular and cellular structures, and a decline in the functional capacity of organs and systems. All of this stimulates the development of new strategies for maintaining healthy and active longevity through agents exerting polyvalent effects on the main pathophysiological mechanisms of age-associated changes. The discovery of the gene responsible for the synthesis of the protein that slows aging, named after the goddess who spins the thread of life-Klotho-sparked great interest among biologists and specialists in theoretical and clinical medicine. The geroprotective action is based on the inhibition of four pathways: 1) insulin-like growth factor-1 of the Klotho protein (IGF-1), 2) transforming growth factor-β1 (TGF-β1), 3) Wnt and 4) nuclear transcription factor (NF-κB). Their activation is associated with inflammation, oxidative and nitrosative stress, reduced autophagy, immune dysfunction, mitochondrial dysfunction, neoplasia, cellular senescence, apoptosis and premature cell death, a decline in the morphofunctional reserves of various organs and systems, and reduced adaptive mechanisms and resistance of the organism to adverse external and internal factors. The review provides a concise description of the anti-aging protein Klotho, considers its biological activity and the dynamics of its serum levels depending on age and on the functional state of the organism under normal and pathological conditions. It is shown that its serum level can be increased by certain medicinal agents and by adherence to healthy lifestyle factors, including work-rest balance, regular physical activity and sports, diet, healthy sleep, and others. Conclusions: The Klotho protein plays an important role in the regulation of aging processes and the development of age-related diseases and therefore may serve as a target for the search and development of medicinal agents that increase its production for the prevention of early aging and the treatment of age-associated pathologies. The multifunctional Klotho protein may represent a new and economically justified biomarker of aging and an integral tool for qualitative and quantitative assessment of lifestyle, biological age, and overall health status.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic drivers in human cancer and are associated with poor prognosis, limited therapeutic options, and frequent resistance to standard treatments. The approval of the first direct KRAS G12C inhibitors demonstrated that mutant KRAS can be targeted clinically, but their efficacy is restricted to a narrow allelic subset and is limited by adaptive resistance. This review summarizes recent advances in KRAS-targeted drug development beyond G12C and outlines emerging strategies designed to improve therapeutic outcomes. A comprehensive literature review was conducted using preclinical and clinical data from studies investigating KRAS inhibitors, rat sarcoma (RAS) pathway modulators, and rational drug combinations. Particular attention was given to allele-specific agents, pan-RAS inhibitors, feedback signaling mechanisms, and resistance biology. Next-generation KRAS inhibitors targeting non-G12C alleles, including KRAS G12D selective agents, have demonstrated potent preclinical activity but remain susceptible to feedback mitogen-activated protein kinase (MAPK) reactivation. Pan-RAS inhibitors that bind the active RAS-GTP state show activity across multiple alleles and tumor types, although toxicity and therapeutic window remain key concerns. Indirect strategies targeting SHP2, SOS1, and downstream MAPK components enhance pathway suppression and delay resistance, especially in combination with direct KRAS inhibitors. Resistance mechanisms encompass secondary KRAS mutations, bypass signaling through alternative RAS isoforms, and activation of parallel pathways. Comutations such as STK11 or KEAP1 further influence therapeutic response and immune contexture. KRAS-directed therapy is rapidly expanding beyond G12C, with allele-specific inhibitors, pan-RAS approaches, and rational combinations offering new opportunities for broader clinical benefit. Ongoing challenges include toxicity management, resistance evolution, and the development of predictive biomarkers to guide therapy selection.

Antimicrobial peptides have emerged as a potential alternative to traditional small-molecule antimicrobials. They possess broad-spectrum efficacy and increasingly confront the challenges of bacterial resistance, especially the adaptive resistance of biofilms. However, advanced rational peptide design methods are still required to ensure optimal property profiles of such peptides, while limiting the cost of their synthesis and screening. Here, we present a computational pipeline for the rational de novo design of antimicrobial and antibiofilm peptides based on an explainable artificial intelligence (XAI) framework. The developed framework combines a Wasserstein Autoencoder (WAE) and a nonlinear dimensionality reduction method─generative topographic mapping (GTM). The WAE was used to learn the latent representation of the peptide space, while the GTM guided the generation of novel AMPs through an illustrative depiction of the latent space in the form of 2D maps. The generated peptides were subjected to screening by machine learning models, resulting in the final hit list based on their predicted activity. The efficacy of the peptides generated with the developed pipeline was experimentally verified by synthesis and testing for activity against methicillin-resistant Staphylococcus aureus (MRSA), achieving a 100% hit rate in targeting biofilms. Notably, the most potent antibiofilm peptide developed in this study demonstrated almost one order of magnitude improvement in IC50 value compared with the potent antibiofilm peptide reference "1018", used as a positive control. The developed pipeline is readily extendable for the optimization of additional peptide properties, including cytotoxicity, tendency to aggregate, and proteolytic stability, underscoring its potential utility for rational design of the peptide-based therapeutics.

This study addresses the urgent need to strengthen inclusive character education in Islamic boarding schools as a response to rising religious intolerance and identity-based exclusivism in Indonesia. Focusing on Pabelan Islamic Boarding School in Magelang, Indonesia, the research employs a qualitative case study design, using participatory observation and in-depth interviews with ustadz, managers, and students. Data were analyzed thematically following the Miles and Huberman model and validated through source triangulation and member checking. Findings reveal four key strategies: integration of national values into the curriculum, inter-mazhab tolerance, non-violent discipline, and respect for local culture-collectively fostering a politically, religiously, psychosocially, and culturally inclusive environment. Students’ responses fell into three patterns: active acceptance, selective adaptation, and passive resistance, with most embracing inclusivity as aligned with rahmatan lil ‘alamin. Despite challenges; structural (limited infrastructure), cultural (homogeneous dominance), and pedagogical (conventional methods), the pesantren demonstrates strong potential as an agent of religious moderation. Theoretically, this study contributes to the discourse on Islamic education by repositioning inclusivity not as a modern import but as an essential, indigenous dimension of Islamic epistemology, thereby expanding the application of character education frameworks within faith-based institutions in pluralistic societies.

Bone remains one of the most hospitable-and devastating-destinations for metastatic cancer cells. At the center of this unwelcome alliance is transforming growth factor‑β (TGF‑β), a cytokine stored in the mineralized matrix and unleashed during osteoclastic bone resorption. Once activated, TGF‑β fuels a self‑reinforcing "vicious cycle": it co‑opts tumor cells to undergo epithelial‑to‑mesenchymal transition, recruits and primes osteoclasts, suppresses osteoblast function, and shapes an immunosuppressive niche that shields malignant clones. The result is a micro‑environment exquisitely tuned for tumor survival, skeletal destruction, and therapy resistance. This review traces the molecular choreography of TGF‑β signaling within the bone tumor microenvironment (TME), detailing its crosstalk with osteogenic, immune, and stromal compartments across breast, prostate, and lung cancer metastases. We synthesize pre‑clinical and clinical efforts to interrupt this pathway, ranging from ligand-neutralizing antibodies and activin receptor-like kinase 5 (ALK5) kinase inhibitors to antisense oligonucleotides and tumor-selective ligand traps-and examine why benefits observed in early trials are tempered by dose‑limiting toxicities and adaptive resistance. Beyond TGF‑β itself, we highlight parallel targets in the TME, including receptor activator of nuclear factor kappa-B ligand (RANKL)‑driven osteoclastogenesis, vascular endothelial growth factor/fibroblast growth factor (VEGF/FGF)‑mediated angiogenesis, and immune checkpoints such as PD‑1, TIM‑3, and LAG‑3, arguing that multi‑pronged combinations guided by real‑time TME profiling offer the most promising path forward. We outline pressing research priorities: mapping the spatiotemporal dynamics of TGF‑β activation, identifying predictive biomarkers for patient stratification, and engineering bone‑targeted delivery systems that preserve normal tissue repair. By decoding and disrupting the TGF‑β‑centered circuitry of bone metastasis, we can move closer to therapies that not only palliate skeletal complications but also prolong life for patients with advanced cancer.