A conserved eIF1A+ luminal cell-centered hypoxic and cold tumor microenvironment promotes prostate cancer progression among different subtypes

Prostate cancer (PCa) is a malignancy with high heterogeneity arising from tumor microenvironment (TME) and histological subtypes. To achieve superior clinical efficacy, it is imperative to identify unified progression drivers within such heterogeneity. Here, we applied imaging mass cytometry to stain 38 proteins on paracancerous, low-grade acinar adenocarcinoma (LgPAC), high-grade PAC (HgPAC), intraductal carcinoma (IDC) and ductal adenocarcinoma (DAC) tissues, identifying that established oncogenic factors (e.g., BRCA1, PSMA) showed limited capacity in distinguishing PCa prognosis; in contract, eIF1A, a key translational initiation factor, was specifically over-expressed in high-risk subtype including HgPAC, IDC and DAC, and correlated with tumor progression and poor prognosis. eIF1A+ luminal epithelium (LE) demonstrated elevated expression of HIF-1a and its downstream targets, along with increased spatial exclusion of anticancer immune cells including PD1- T cells and CD163- macrophages, which were validated by single-cell RNA sequencing (RNA-seq) analysis. Mechanistically, EIF1A knockdown or translation inhibitor homoharringtonine (HHT) impaired HIF-1a translation without affecting its transcription in vitro, and reduced tumor volume in preclinical subcutaneous tumor models, with RNA-seq and multiple immunofluorescence (mIF) analyses confirming significant suppression of hypoxia-associated pathways. Based on an ongoing investigator-initiated trial of PCa patients receiving neoadjuvant HHT combined with androgen deprivation, we observed pronounced inhibition of hypoxia and enhanced immune cell infiltration upon treatment through single-cell RNA-seq of 16 surgical tissues and mIF analyses. This study applies spatial proteomics to delineate conserved molecular features across histological subtypes, providing insights for the clinical management of PCa.