Breast cancer bone metastasis is a common and devastating complication among patients with advanced breast cancer, marked by aggressive tumor growth and extensive osteolytic destruction. Effective treatment requires simultaneous elimination of tumor cells and restoration of bone tissue. To address this challenge, we developed a bone-targeting nanomaterial, CPPA NPs, composed of a polydopamine-coated calcium peroxide core embedded with palladium nanoparticles, and functionalized with phytic acid for bone affinity. This design integrates calcification and photothermal activity to achieve synergistic tumor inhibition and bone repair. Within the acidic tumor microenvironment, CPPA NPs release Ca2+ and H2O2, triggering mitochondrial calcium overload and oxidative stress in cancer cells. In the presence of exogenous phosphate, this process drives extensive tumor cell calcification, substantially reducing cell viability. Under 808 nm laser irradiation, the photothermal effect accelerates Ca2+ and H2O2 release, further enhancing calcification and inducing widespread tumor cell death. Laser treatment promotes osteoblast differentiation, supporting bone regeneration. In a murine breast cancer bone metastasis model, the combined calcification-photothermal therapy markedly suppressed tumor burden, mitigated osteolytic lesions, and promoted new bone formation. Together, these findings establish CPPA NPs as a promising therapeutic platform capable of integrating potent antitumor efficacy with osteogenic regeneration, offering a dual-functional strategy for the treatment of breast cancer bone metastasis.

This study aimed to develop prognostic models of distant metastasis (DM) and bone metastasis (BM) in invasive breast cancer (IBC) incorporating whole-tumor radiomics, intratumoral heterogeneity (ITH) metrics. A total of 1097 patients with IBC from three centers were included and divided into a training cohort (n = 610), a validation cohort (n = 153), and two independent testing cohorts (n = 170 and n = 164). Whole-tumor radiomic features were extracted from two-dimensional regions of interest (ROIs) on mammography and three-dimensional ROIs on the second post-contrast phase of dynamic contrast-enhanced MRI, while ITH metrics were derived from enhancement-based subregions. Predictive performance was assessed for each model, and the resulting risk scores were further used for risk stratification analyses. SHapley Additive exPlanations (SHAP) were used to assess the importance of individual ITH metrics and to quantify the contributions of each component within the combined model. The combined model achieved the highest concordance index and robust risk stratification performance for both DM and BM. SHAP analysis indicated that the radiomics-based risk score ranked as the most influential predictor across both endpoints, while the ITH score consistently showed higher relative importance for BM than for DM. Distance-, shape-, and topology-related ITH metrics were among the most influential contributors across both endpoints. The combined model demonstrated robust prognostic performance, and the differential contribution of the ITH score between DM and BM indicates a more prominent role of imaging-derived heterogeneity in BM.

Glypican-1-targeted antibody-drug conjugate shows therapeutic efficacy in lung squamous cell carcinoma.

Targeting breast cancer senescence in 3D models of bone metastasis.

MDA-9/Syntenin small molecule inhibitor IVMT-Rx-4 blocks prostate cancer bone metastasis.

Mammary tumor cells reshape the bone marrow niche inducing B cell lossBone marrow B cell development is impaired in mammary tumor metastasisExperimental depletion of B cells promotes bone metastasisG-CSF mediates B cell loss in mammary tumor metastasis.

Bone marrow(BM) is the primary site of hematopoiesis, supporting the self-renewal and differentiation of hematopoietic stem cells (HSCs). Its function depends on a highly complex microenvironment composed of stromal cells, vascular networks, extracellular matrix components, and dynamic biophysical signals. Traditional two-dimensional culture systems and animal models fail to adequately recapitulate the spatial architecture and dynamic regulatory processes of the human bone marrow niche, thereby limiting in-depth investigations into hematopoietic regulatory mechanisms, disease pathogenesis, and drug-induced bone marrow toxicity. In recent years, advances in microphysiological systems (MPS) have provided novel engineering approaches for the in vitro reconstruction of the bone marrow microenvironment. This review systematically summarizes current construction strategies for bone marrow MPS, including three-dimensional self-organized bone marrow organoids and microfluidic bone marrow-on-a-chip platforms. Particular attention is given to the roles of key cellular components, biomaterial scaffolds, vascularized architectures, and dynamic perfusion systems in biomimetic bone marrow engineering. In addition, we discuss strategies for constructing more complex models, such as vascular niches, vascularized bone tissue constructs, and bone metastasis models. Bone marrow MPS more faithfully recapitulate the hematopoietic microenvironment and provide a physiologically relevant in vitro platform for hematopoietic research, disease modeling, and drug evaluation, thereby supporting future advances in precision and regenerative medicine.

Accumulating evidence shows that bacteria influence cancer homeostasis, yet the effects of tumor‑associated microbes and their products remain largely unexplored. We previously reported that P. aeruginosa–cancer crosstalk suppresses tumors via the bacterial cupredoxin azurin, and we developed an azurin‑derived peptide that was tested in clinical trials. Building on our previous studies, we studied tumor-resident bacteria for novel therapeutics and targets. Photosynthetic bacteria from the phylum Chloroflexota, including a member of the class Chloroflexia, identified in tumors, carry the cupredoxin auracyanin gene. Based on the structural and chemical characteristics of auracyanin, we designed a novel cell-penetrating peptide, aurB. Plant chloroplasts are thought to have evolved from a bacterial endosymbiont, and both chloroplasts and mitochondria possess shared proteins essential for ATP-dependent energy production, indicating that these bacterial-derived proteins may influence mitochondrial function. Consistent with this model, we demonstrated that aurB, a peptide from cupredoxin auracyanin B, localized at mitochondria, blocked energy production by targeting ATP synthase in prostate cancer cells, thereby significantly inhibiting tumor growth. More strikingly, combination treatment with aurB and radiation therapy significantly inhibited tumor growth in a tibial bone metastasis model. Moreover, the number of metastatic lesions in the lungs was also significantly lower upon aurB treatment. Multiplex RNA-expression profiling revealed that the inhibition of ATP production by aurB increased the efficacy of radiation therapy by modulating multiple pathways involving HIF-1α. Our findings indicate that electron transfer proteins could represent an important source of promising novel peptide-based agents that target the aberrantly activated mitochondrial energy system in cancer.

Patients with breast or prostate cancer have a high chance of developing bone metastasis, which is associated with many skeletal-related events. The development of novel bone metastasis treatments is lagging behind due to the lack of reliable models. We aimed to develop a humanized bone metastasis model comprising vital human bone discs and human metastatic cancer cells (bone metastasis discs), which were subsequently cultured ex vivo or subcutaneously implanted into nude mice. Ex vivo culture experiments confirmed that cells within the bone metastasis discs remained metabolically active, while the presence of metastatic cancer cells could be monitored using bioluminescence. Although histological analyses confirmed the presence of relevant bone cells in the human bone tissue, no apparent formation of metastatic lesions was detected over the 2-week ex vivo culture period. In contrast, subcutaneously implanted bone metastasis discs demonstrated clear metastatic lesion formation, with osteolytic characteristics, that progressed from 3 to 6 weeks after implantation for both breast and prostate cancer bone metastasis discs. Histologically, healthy bone tissue with bone marrow compartments as well as anastomosis was observed. Cisplatin treatment of ex vivo cultured bone metastasis discs significantly decreased the bioluminescent signal from (prostate) cancer cells, while no effects of cisplatin treatment were observed for invivo implanted bone metastasis discs. Our data provide a proof of concept for an ex vivo/invivo bone metastasis model with vital human bone and human metastatic cancer cells but require further fine-tuning to improve robustness, relevance, and quantification methods. Future research could potentially use these models for the evaluation of novel bone metastasis treatments, accelerating their potential clinical application.

A neuraminidase-functionalized injectable hydrogel depletes sialic acid to disrupt the tumor-osteoclast cycle and suppress breast cancer bone metastasis.

SNHG18 deficiency reprograms arginine metabolism to foster an immunosuppressive microenvironment in prostate cancer bone metastasis.

Bone metastasis represents a frequent late-stage complication in cancers such as lung, breast, and prostate, severely affecting patients’ quality of life. Conventional two‑dimensional cultures and animal models fail to recapitulate the complex bone microenvironment. Patient-derived organoids (PDOs) offer a physiologically relevant three-dimensional platform to recapitulate bone metastasis by preserving native tumor features and modeling tumor–bone interactions. This review systematically outlines the current methodologies for constructing bone metastatic organoid models, evaluates their applications, and identifies future directions. We describe the essential components of culture systems and critically discuss their strengths and limitations in modeling bone‑specific signaling. Furthermore, we highlight the capacity of PDOs to elucidate key aspects of bone metastasis, including tumor cell adaptation to the osseous niche, bidirectional remodeling of the microenvironment, and the dynamic monitoring of disease progression. Bone organoids are also discussed as a means of establishing a standardized bone microenvironment, offering a controllable in vitro platform for investigating interactions between tumor cells and the bone matrix. Furthermore, we present the translational potential of organoids for informing individualized therapy selection, evaluating clinical drug sensitivity, and facilitating the development of organoid biobanks. Looking forward, the development of patient-specific “bone metastasis-on-a-chip” systems with artificial intelligence-driven digital twins may transform the research paradigm from experimental simulation to precision prediction, ultimately advancing personalized therapeutic strategies for bone metastatic disease.

Excessive bone disruption, driven by upregulation of bone-degrading osteoclasts, occurs in several pathologies, including breast cancer osteolytic bone metastasis, a condition associated with poor prognosis and diminished quality of life for patients. The matricellular protein thrombospondin-1 (TSP-1) plays pleiotropic roles in physiological and pathological remodeling of several tissues, including bone, and in shaping the microenvironment of primary tumors and metastasis. This study aimed to explore the role of TSP-1 in bone remodeling associated with osteolytic bone metastasis. We have identified a C-terminal fragment of TSP-1, E123CaG, that inhibited RANKL-induced osteoclast differentiation. Cleavage of TSP-1 by serine proteases released by mature osteoclasts, particularly HTRA1, generated a similar fragment, indicating a possible role as a feedback mechanism of control. E123CaG bound RANK, the RANKL receptor on osteoclast precursors, and impaired early (the MAPKs p38 and JNK) and late (NFATc1) downstream signaling. E123CaG also bound osteoprotegerin (OPG), the decoy receptor of RANKL, in this case further potentiating its inhibitory activity by protecting it from degradation by proteases, including HTRA1. In an in vivo model of osteolytic bone metastasis, the expression of E123CaG by murine breast cancer cells reduced osteolytic lesions and prolonged survival, indicating that the C-terminal TSP-1 fragment is also active in vivo and can protect the bone against metastasis-associated osteolysis. Our findings indicate that the release in the bone environment of this TSP-1 fragment, with its unique dual ability to inhibit RANK signaling while potentiating OPG activity, represents an important mechanism to control bone remodeling in osteolytic bone metastasis.

Metastatic prostate cancer (PCa), especially when it involves the bone, remains a significant clinical challenge with limited therapeutic options. Our recent research identified Myeloid Differentiation Protein-2 (MD2/LY96) as a potential biomarker associated with poor prognosis and higher metastatic potential in PCa. In this Research Perspective, we build on those findings and present new preclinical data showing that pharmacological inhibition of MD2 markedly reduces tumor growth in a PCa mouse model of bone metastasis. Analysis of patient tumor tissues demonstrated that high MD2 expression is associated not only with metastasis but also with increased infiltration of T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), indicating a role in promoting an immunosuppressive environment. Additionally, we show that soluble MD2 (sMD2) may serve as a non-invasive biomarker of metastatic burden and help predict resistance to poly ADP-ribose polymerase (PARP) inhibitor therapy.This Research Perspective aims to consolidate mechanistic and preclinical evidence supporting MD2 as a driver of prostate cancer metastasis and to evaluate the therapeutic potential of pharmacological MD2 inhibition in a bone metastasis model.These findings support MD2 as a novel therapeutic target and identify soluble MD2 as a promising predictive and prognostic biomarker in metastatic PCa, with mechanistic links to immune evasion and inflammatory signaling.

Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active 'evolutionary gateways' that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic-Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment.

Rationale: Radium-223 dichloride (223RaCl2) is an FDA-approved alpha-emitting radiopharmaceutical that targets bone metastases in metastatic castration-resistant prostate cancer (mCRPC). This study investigates the therapeutic and immunological effects of combining 223RaCl2 with immune checkpoint inhibitors (ICIs) in a clinically relevant, immunocompetent murine model of prostate cancer bone metastasis. Methods: Luciferase-expressing MyC-CaP prostate cancer cells were implanted intratibially into FVB mice to establish bone metastases. Mice were treated with escalating doses of 223RaCl2 (0.04–0.27 µCi) alone or a single dose combined with anti-CTLA-4 and anti-PD-L1 ICIs. Tumor growth was monitored using bioluminescence imaging. Micro-CT, alpha camera imaging, histology, and qPCR were used to assess bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression. Ex vivo biodistribution and blood analyses quantified tissue uptake and toxicity. Results: Escalating doses of 223RaCl2 did not significantly inhibit tumor growth or improve survival. Biodistribution and imaging showed preferential localization of 223RaCl2 to tumor-adjacent bone, with minimal signal in isolated tumor tissue. Immunohistochemistry revealed increased CD4+ and CD8α+ T-cell infiltration in regions of high γH2AX expression, indicating localized immune modulation. However, combination therapy with ICIs did not enhance tumor control or immune infiltration beyond monotherapy. qPCR demonstrated significant upregulation of Mhc1 only in the combination group, suggesting localized immune activation. Toxicity profiles remained acceptable. Conclusions: 223RaCl2 localizes primarily to bone surfaces, limiting direct cytotoxic and immunomodulatory effects within the tumor microenvironment. While combination with ICIs did not improve efficacy, these findings provide a platform for studying spatial dose distribution and support future development of tumor-targeted alpha therapies to potentiate immunotherapy in mCRPC.

Membrane-proximal binding of PSMA facilitates synapse formation with CAR and enhances antitumor activity of PSMA CAR-T cells against prostate cancer.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, yet it remains largely ineffective against bone metastases. The immunosuppressive bone marrow microenvironment is a major barrier to ICB success in bone metastasis. Herein, we developed an implantable dual-drug depot using a gelatin methacryloyl (GelMA) scaffold to prevent tumor recurrence and progression following surgical resection. The GelMA scaffold is co-loaded with MSA-2, a non-nucleotide agonist of stimulator of interferon genes (STING), and calcium carbonate (CaCO3) microparticles (MPs) encapsulating B7-H3 antibodies (αB7-H3-MPs). After implantation at the bone metastasis site, the scaffold provides sustained releases of MSA-2 and αB7-H3-MPs. MSA-2 is released first to activate the STING signaling pathway, triggering interferon secretion, reprogramming immunosuppressive cells, and promoting effector T cell infiltration and activation. Subsequently, dissolution of CaCO3 microparticles in the acidic tumor microenvironment facilitates the subsequent release of αB7-H3, which blocks the B7-H3 checkpoint upregulated by STING activation and prevents T-cell exhaustion. This sequential release strategy was validated in multiple bone metastasis models, confirming its ability to produce a sustained and potent local antitumor immune response while reducing systemic toxicity associated with STING agonists and ICB drugs. Therefore, the scaffoldMSA-2 αB7-H3-MP represents a promising localized immunotherapy approach for the treatment of bone metastasis.

A pan-cancer single-cell transcriptomic atlas of human bone metastases.

Digital spatial profiling of α-PD-1 treated breast cancer bone metastases reveals region-specific signaling and enrichment of immune-suppressive markers