Single-cell and spatial transcriptomics highlight the characteristics of club cells and their interactions within the tumor microenvironment in prostate cancer

Prostate cancer, a paradigm of heterogeneity, is a disease marked by striking diversity in biological subtypes—each with distinct molecular signatures and a broad spectrum of prognostic outcomes. Our study aimed to characterize club cells and their interactions within the tumor microenvironment in both prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Single-cell RNA sequencing datasets of normal prostate tissues, PCa, and CRPC were retrieved from the Gene Expression Omnibus (GEO) database. Club cells were identified based on their canonical biomarkers. Comprehensive single-cell analyses, including gene set variation analysis (GSVA), pseudotime analysis, and phenotypic correlation analysis, among others, were employed to delineate their characteristic features. Club cells showed relatively low AR expression and were most consistently associated with biochemical recurrence rather than with disease progression or metastasis in phenotype-correlation analyses. In both PCa and CRPC, club cells displayed transcriptional programs consistent with higher predicted resistance to enzalutamide and docetaxel and lower predicted resistance to abiraterone. CRPC samples contained a higher proportion of club cells than PCa samples. Ligand-receptor and pathway-based analyses further predicted broad communication between club cells and immune/stromal compartments, including putative interactions involving exhausted T cells. This study identifies club cells as a recurrent epithelial state linked to biochemical recurrence, therapy-associated transcriptional programs, and potential tumor-microenvironment communication in PCa and CRPC. These results refine the cellular context of recurrence and immunosuppression and provide testable hypotheses for future functional studies.