Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival and could inform precision therapeutic strategies for PCa.
Abstract
Prostate cancer (PCa) frequently metastasizes to bone, marking incurable disease. This progression is driven by an immunologically cold bone tumor microenvironment that fosters resistance to therapy. To define the mechanisms underlying this uniquely immunosuppressive niche, we applied spatial single cell analyses across primary tumors and metastatic sites. Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival. Tumor-intrinsic IFN-I expression correlated with memory T cell infiltration, whereas the bone myeloid compartment was enriched for protumor macrophages and showed reduced dendritic cell (DC) activation and antigen presentation. Digital spatial profiling of matched tumors revealed a broad loss of IFN-I-regulated immunostimulatory and checkpoint molecules. Notably, B7-H3, a putative negative regulator of IFN-I, was highly expressed in bone metastases and inversely associated with antigen presentation. These findings define bone-specific mechanisms of immune resistance and highlight therapeutic vulnerabilities that could inform precision therapeutic strategies for PCa.
This study comprehensively maps the coevolution of malignant thyrocyte plasticity and the immunosuppressive metastatic niche in thyroid cancer and provides a robust molecular rationale for developing next-generation immunotherapeutic strategies tailored to thyroid cancer.
Shu-hang Xu, Yaorong Su, Senmin Zhang et al.· Oncoimmunology· 0 citations
Intrahepatic metastasis in multifocal hepatocellular carcinoma is associated with poor prognosis and therapeutic resistance, yet the immune mechanisms driving disease progression remain unclear. Here, we analyzed genetic and immune differences between primary tumors and intrahepatic metastatic lesions using sequencing approaches and spatial validation methods. We found that metastatic lesions shared key genomic features with primary tumors but exhibited a distinct immunosuppressive environment enriched in myeloid and T cell populations. In particular, a subset of macrophages expressing glycoprotein nonmetastatic melanoma protein B (GPNMB) was consistently enriched in metastatic niches across multiple independent cohorts. These macrophages were spatially colocalized with CD8+ T cells exhibiting features of terminal exhaustion. Mechanistically, integrated multiomics and functional analyses revealed that GPNMB overexpression triggers lipid metabolic rewiring via the phosphatidylinositol 3-kinase/AKT-cyclooxygenase-2 cascade, leading to elevated prostaglandin E2 secretion, which directly suppresses CD8+ T cell cytotoxicity. Specific silencing of this subset using a dual-targeted, lipid-polymer nanoparticle (APLsiGpnmb) effectively reversed T cell exhaustion, inhibited metastasis, and synergized with anti-programmed death 1 immunotherapy in mouse models without inducing systemic toxicity. These findings identify GPNMB-positive macrophages as key metabolic and immune regulatory hubs, suggesting that targeting the GPNMB–prostaglandin E2 axis provides a promising precision therapeutic strategy for intrahepatic metastasis in multifocal hepatocellular carcinoma.
Yuyan Xu, Cheng Zhang, Zhuo-Cheng Ji et al.· Research· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
Bone metastases (BoMs) are a major clinical challenge across cancer types, yet mechanistic insights remain limited by small cohorts and insufficient profiling depth. Here, we present a single‐cell RNA sequencing atlas of 95 BoMs, 22 healthy bone marrows (hBMs) and 129 primary tumors (PTs) spanning 10 cancer types, comprising 895,475 high‐quality transcriptomes, to map cellular remodeling during bone metastatic colonization. Malignant cells in BoMs converged on chromosomal instability—high proliferative states with enhanced angiogenic programs and suppressed immune‐inflammatory and metabolic pathways. The BoM immune landscape featured reduced cytotoxic lymphoid populations and expanded exhausted T‐cell states, with pronounced cancer type‐specific heterogeneity. BoM‐resident myeloid cells showed marked suppression of antigen presentation and phagocytosis, indicating immunosuppressive reprogramming. Stromal remodeling was characterized by enrichment of immunosuppressive CAFs, depletion of antigen‐presenting fibroblasts, reduced mesenchymal MHC expression, and expanded angiogenic endothelial programs. Cell–cell communication analyses predicted strengthened CXCL12–CXCR4 stromal–immune signaling. In vitro, the CXCL12–CXCR4 axis recruited CD8
+
T cells and enhanced their adhesion, spatially sequestering them from the tumor parenchyma, while CXCR4 blockade or CXCL12 knockdown significantly reduced tumor‐cell migration and invasion in vitro. This atlas defines convergent hallmarks of bone metastasis and highlights shared stromal–immune dependencies as therapeutic vulnerabilities.
Yitong Pan, Zhou Yang, Junyuan Deng et al.· iMetaMed· 0 citations
BACKGROUND
Prostate cancer (PCa) bone metastases cause significant morbidity and mortality in advanced disease. The tumor microenvironment (TME) of bone metastases drives disease progression and therapeutic resistance, yet comprehensive characterization of its cellular heterogeneity remains limited. This study aims to characterize cellular populations and molecular signatures of PCa bone metastases using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database.
METHODS
scRNA-seq data from PCa bone metastasis samples were obtained from GEO. Quality control, normalization, dimensionality reduction, and cell type identification were performed using Seurat. Differential expression, pseudotime trajectory, pathway enrichment, gene regulatory network, and cell-cell communication analyses were conducted to investigate molecular mechanisms of bone metastasis progression.
RESULTS
Single-cell analysis identified distinct cellular populations within the bone metastatic TME, including malignant epithelial cells, fibroblasts, endothelial cells, osteoblasts, osteoclasts, and immune cells. Clustering revealed heterogeneous transcriptional signatures, while pseudotime analysis uncovered developmental transitions between cell states. Key transcription factors, enriched pathways related to bone remodeling, angiogenesis, and immune regulation, and critical signaling interactions between cancer and stromal cells were identified.
CONCLUSION
This study provides comprehensive insights into the cellular composition and molecular architecture of the PCa bone metastatic TME, revealing distinct cell populations, type-specific gene signatures, and cell-cell communication networks driving bone metastasis progression.
Jun Zhao, Desheng Wu· SLAS technology· 0 citations
It is identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors.
Laiman N. Wu, Janet L. Oblinger, Da-Zhuan Xin et al.· Science Advances· 0 citations