Integrated transcriptomics and single-cell analysis identify ITGAX⁺ macrophages as key immunosuppressive factors in the prostate cancer tumor microenvironment

Prostate cancer (PCa) is a leading cause of cancer-related death in men worldwide. The tumor microenvironment (TME), particularly its immune and stromal components, has a critical influence on PCa progression and patient outcomes. Identifying novel TME-associated biomarkers is important for better understanding PCa progression and may inform future diagnostic or therapeutic strategies. Transcriptome data from the TCGA-PRAD cohort (499 tumor and 52 normal prostate samples) were analyzed using ESTIMATE and immune deconvolution algorithms, integrated with clinical and survival data. Candidate genes were identified through differential expression, Cox regression, and PPI network analysis, followed by survival and GSEA functional prediction. Single-cell RNA sequencing further delineated gene expression patterns and immune functions within the TME. Integrin subunit αX (ITGAX) emerged as a prognostic gene closely linked to advanced clinicopathological features and poor progression-free survival. High ITGAX expression correlated with increased M2 macrophages and reduced activated NK cells. Single-cell analysis revealed that ITGAX is enriched in macrophage subsets, consistent with a terminally differentiated phenotype associated with immunosuppressive signatures. Cell–cell communication analysis demonstrated extensive inhibitory interactions between ITGAX⁺ macrophages and CD4⁺, CD8⁺, and Treg cells, suggesting potential inhibitory interactions with T cells and a role in shaping an immunosuppressive TME. ITGAX marks a macrophage population associated with an immunosuppressive TME and poor prognosis in PCa. These findings highlight that ITGAX⁺ macrophages may contribute to immune evasion and represent potential targets for future therapeutic investigation.