Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing–like response of ECM–receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)–tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Background: Aberrant DNA methylation is an early event during tumorigenesis. In the present study, we aimed to construct a methylation diagnostic tool using urine sediment for the detection of urothelial bladder carcinoma, and improved the diagnostic performance of the model by incorporating single-nucleotide polymorphism (SNP) sites. Methods: A three-stage analysis was carried out to construct the model and evaluate the diagnostic performance. In stage I, two small cohorts from Xiangya hospital were recruited to validate and identify the detailed regions of collected methylation biomarkers. In stage II, proof-of-concept study cohorts from the Hunan multicenter were recruited to construct a diagnostic tool. In stage III, a blinded cohort comprising suspicious UBC patients was recruited from Beijing single center to further test the robustness of the model. Results: In stage I, single NRN1 exhibited the highest AUC compared with six other biomarkers and the Random Forest model. At the best cutoff value of 5.16, a single NRN1 biomarker gave a diagnosis with a sensitivity of 0.93 and a specificity of 0.97. In stage II, the Random Forest algorithm was applied to construct a diagnostic tool, consisting of NRN1, TERT C228T and FGFR3 p.S249C. The tool exhibited AUC values of 0.953, 0.946 and 0.951 in training, test and all cohorts. At the best cutoff value, the model resulted in a sensitivity of 0.871 and a specificity of 0.947. In stage III, the diagnostic tool achieved a good discrimination in the external validation cohort, with an overall AUC of 0.935, sensitivity of 0.864 and specificity of 0.895. Additionally, the model exhibited a superior sensitivity and comparable specificity compared with conventional cytology and FISH. Conclusions: The diagnostic tool exhibited a highly specific and robust performance. It may be used as a replaceable approach for the detection of UBC.

Testicular germ cell tumors (TGCTs) are the most common solid malignant tumor in young men aged 20–34 years. Currently, the diagnosis and differentiation of TGCTs depend on immunohistochemical analysis, and the treatment methods are mainly surgery and chemoradiotherapy. Although immunotherapy has been applied in clinic, the response rate is not high, and also there is a lack of effective biomarkers. In this study, through high‐throughput transcriptome sequencing and public data mining, the expression of hepatitis A virus cellular receptor 2 (HAVCR2) was found to be significantly upregulated in TGCT tissue and correlated with poor prognosis. Additionally, the expression level of HAVCR2 was negatively correlated with its DNA methylation but positively correlated with its copy number level. The HAVCR2 expression level was significantly positively correlated with the infiltration of six types of immune cells, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Also, the higher its expression level, the higher the immune cell abundance. Tumor immune dysfunction and exclusion (TIDE) scoring analysis showed that HAVCR2 was related to the responsiveness to TGCT immunotherapy. Drug sensitivity analysis revealed that HAVCR2 was related to the sensitivity of multiple antitumor drugs. This study demonstrated that HAVCR2 has high potential as a biomarker for the diagnosis, prognosis, and treatment of TGCTs.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor survival after standard treatment. Although genomic alterations of PSCC have been characterized in several latest studies, the association between the formation of somatic landscape and regional lymph node metastasis (LNM), an important predictor for patient survival, has not been comprehensively investigated. Here, we collected formalin-fixed paraffin-embedded tumor tissue and matched normal samples of 32 PSCC patients, including 14 LNM patients and 18 clinically node-negative patients, to implement a whole-exome sequencing. Comparison of genomic features among different lymph node status subgroups was conducted after genomic profiling and its effects on patient survival were explored. Top-ranked recurrent gene mutants in our PSCC cohort were TP53 (13/32), NOTCH1 (12/32), CDKN2A (11/32), TTN (9/32) and FAT1 (8/32), mainly identified in the Notch, Hippo, cell cycle, TP53, RTK-RAS and PI3K pathways. While CDKN2A was confirmed to be the driver gene in all PSCC patients, certain gene mutants were significantly enriched in LNM involved patients, including TP53 (9/14 vs. 4/18, p = 0.029) and GBF1 (4/14 vs. 0/18, p = 0.028). Overall survival stratification of PSCC patients were found to be significantly correlated with mutations of three genes, including PIK3CA (Hazard ratio [HR] = 4.15, p = 0.029), CHD7 (HR = 4.82, p = 0.032) and LAMC3 (HR = 15.9, p < 0.001). PIK3CA and LAMC3 held a higher prevalence in patients with LNM compared to those without LNM (PIK3CA: 3/14 vs. 1/18, LAMC3: 2/14 vs. 1/18). Our finding demonstrated that genomic divergence exists across PSCC patients with different lymph node statuses, and it may be correlated with their survival outcome. It helps delineate somatic evolution during tumor progression and perfect potential therapeutic intervention in this disease.

Testicular sex cord stromal tumor (TSCST) is a rare testicular tumor with unknown molecular mechanisms, tumor microenvironment (TME) and limited therapeutic options. To define the molecular mechanism and potential targets of TSCST, we combined single-cell RNA sequencing with single-cell nuclear RNA sequencing along with spatial transcriptomics from different TSCST tumor regions. This revealed significantly low expression of immune cell genes in tumor areas, indicating an immune-cold tumor environment and a critical epithelial-mesenchymal transition program during tumorigenesis and disease progression. Also, the study identified high expression levels of the androgen receptor (AR) and related genes in tumor cells, suggesting AR inhibitors as potential therapeutic targets. Furthermore, we identified spatial intra-tumoral heterogeneity, with high senescent characteristics. Finally, the study reports that tumor cells might interact with macrophages, promoting M2 polarization through the APP-CD74 ligand-receptor pair, which has promising therapeutic prospects for this disease. Our data provide comprehensive insights into TSCST, including its cold TME, cellular origins, spatial niches, and cell-cell interactions, highlighting that targeting AR signaling might be a potential therapeutic strategy. The online version contains supplementary material available at 10.1186/s40364-026-00924-0.