DIAPH3 is a multifaceted prognostic biomarker that links immunotherapy response to tumor microenvironment in prostate cancer.

[OBJECTIVE] To systematically investigate the prognostic value of DIAPH3 in prostate cancer (PCa) and explore its potential role in linking immunotherapy response and tumor microenvironment remodeling.

[METHODS] We analyzed TCGA-PRAD, Stockholm, Moffitt, UK, and Yinchuan cohorts. DIAPH3 expression was compared between tumor and adjacent tissues. Kaplan–Meier and multivariate Cox analyses were conducted to assess BCRFS and PFS. Immunotherapy response was analyzed using TIDE and IPS. Gene expression, somatic mutations, and immune microenvironment status were analyzed.

[RESULTS] High DIAPH3 expression correlates with poor prognosis and is an independent predictor of BCRFS, PFS, and RFS. Functional analyses show its involvement in cell cycle regulation and IL-17 signaling. Elevated DIAPH3 correlates with altered immune infiltration, including increased Th2 lymphocytes and decreased NK cells and pDCs. DIAPH3 expression associates with immunotherapy response, validated in a pan-cancer cohort. Drug sensitivity analysis revealed PI3K inhibitors are more effective in low DIAPH3 tumors, while PARP inhibitors are more effective in high DIAPH3 tumors.

[CONCLUSION] DIAPH3 is a robust prognostic biomarker in PCa, linked to poor prognosis, immune infiltration, and therapeutic response. High DIAPH3 expression correlates with aggressive tumor progression and poor survival outcomes, highlighting its value for prognostic modeling and therapy selection.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04413-6.