Elevated tumor-associated androgen receptor activity correlates with poor immune infiltration and immunotherapy response across cancer types

Abstract The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. Here, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA-seq (TCGA), single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and ssGSEA. Key findings were validated using Digital Spatial Profiling and immunohistochemistry. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, highest in prostate adenocarcinoma. Genes significantly correlated with AR activity show negative associations and are enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFN-γ pathway activity across tumors and sexes—unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed AR inhibition enhanced immune cell and IFN-γ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.