Background Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. Methods Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid–liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. Results YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. Conclusions Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer–promoter interactions, thereby increasing PCa progression.

Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple cancer types including prostate cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR⁺ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR⁺ and AR^- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.

Background: Prostate cancer (PCa) and Alzheimer’s disease (AD) are age-related disorders with a complex epidemiological association and limited therapeutic options. Identifying shared molecular drivers may reveal new treatment targets. Objective: To identify common transcriptomic signatures between PCa and AD and validate the role of interleukin-11 (IL11) as a functional comorbidity factor. Methods: Multi-cohort transcriptomic datasets (GSE48350, GSE5281 and GSE28146 for AD; TCGA-PRAD, DKFZ2018 and MSKCC for PCa) were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed, followed by a two-tier machine learning pipeline (Random Forest and LASSO Cox regression) to screen overlapping genes. Immune infiltration was evaluated by CIBERSORT and single-cell transcriptomics for PCa. The functional role of IL11 was assessed in RM-1 murine and DU145 human PCa cells using colony formation, wound healing, Transwell assays, and immunocompetent C57BL/6 orthotopic and subcutaneous xenograft models. The cognitive effects of IL11 were evaluated using Morris water maze (MWM) tests, and the neuropathological changes were assessed by detecting hippocampal amyloid-β (Aβ) deposition. Additionally, a cross-sectional analysis was performed in a population cohort (n=215) to investigate the associations between IL11 levels and AD pathological biomarkers. Results: A total of 455 shared candidate genes were identified, and a 10-gene signature (NDRG4, ISG15, IL11, ENO2, DYNC1I1, DNASE1, ATP6V1G2, ATCAY, ANLN, AGAP9) was established. The risk score effectively stratified PCa patients with poor progression-free interval (log-rank P < 0.001; AUC for 1-,3-,5-year = 0.78,0.73,0.70), validated in two external cohorts (DKFZ2018, MSKCC). IL11 was the top candidate and was significantly upregulated in both diseases. High IL11 expression correlated with an immunosuppressive microenvironment, characterized by increased M2 macrophages and regulatory T cells, and with higher tumor mutation burden. Single-cell analysis localized IL11 to a subset of cancer-associated fibroblasts. In vitro , IL11 treatment enhanced PCa cell proliferation, migration, and invasion. In vivo , intraperitoneal IL11 accelerated PCa tumor growth in mice. In the MWM test, IL11-treated mice exhibited significantly longer escape latencies and fewer platform crossings, which were accompanied by increased hippocampal Aβ deposition, suggesting that IL11 induced cognitive dysfunction. Cross-sectional cohort analyses further linked higher serum IL11 to reduced CSF Aβ42 and elevated p-tau181. Conclusion: IL11 acts as a shared risk factor related to PCa progression and cognitive decline in AD, representing a convergent molecular pathway and a potential therapeutic target for both age-related diseases.

Prostate cancer resistance to androgen deprivation therapy often involves neuroendocrine transformation. Using single-cell RNA sequencing of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice across pathological stages (early adenocarcinoma to late neuroendocrine prostate cancer [NEPC]), we find an early neuroendocrine-initiating cluster marked by elevated HOXD11, conserved in human NEPC. Genetic suppression of HOXD11 blocks neuroendocrine differentiation and restores androgen receptor (AR) signaling. Mechanistically, HOXD11 directly activates FOXA2 and N-methyl-D-aspartate receptor (NMDAR) subunits (GRIN1/GRIN3A), pathways upregulated in NEPC and linked to poor prognosis. Pharmacological NMDAR inhibition with memantine suppresses NEPC progression preclinically. Notably, a preliminary clinical observation in one evaluable patient with chemotherapy-failed NEPC shows radiographic regression of primary and metastatic lesions after memantine treatment. These findings establish HOXD11 as a driver of neuroendocrine transformation and support further investigation of memantine as a candidate therapeutic strategy for NEPC.

PCa is a malignancy with high heterogeneity arises from both tumor microenvironment (TME) and histological subtypes. To achieve superior clinical efficacy, it is imperative to identify unified progression drivers within such heterogeneity in PCa, thereby enabling the development of more consistent and effective therapeutic strategies. In this study, we applied imaging mass cytometry to stain 39 proteins on 71 tissues comprising para-cancer, low-grade acinar adenocarcinoma (LgPAC), high-grade PAC (HgPAC), intraductal carcinoma (IDC) and ductal adenocarcinoma (DAC) tissues, obtaining the spatial proteomic landscape of 345,233 single cells. We discovered a hypoxic eIF1A ⁺ luminal epithelial (LE) cluster exhibiting both translational activation and immunosuppressive properties, which was enriched in high-risk PCa including HgPAC, IDC and DAC, and associated which tumor progression and unfavorable prognosis. Additionally, eIF1A ⁺ LE orchestrates the formation of an immunologically “cold” TME, characterized by the low infiltration of anti-cancer immune cells including PD1 ^- T cells CD163 ^- macrophages. Through in vivo validation and investigator-initiated study, we further found that Homoharringtonine, an inhibitor targeting protein translation process, effectively inhibited PCa growth, alleviated hypoxic microenvironment, and enhanced immune cell infiltration. This study is the first to apply spatial proteomics to delineate consistent molecular features across histological subtypes, providing transformative insights for clinical management of PCa.