IL-6/STAT3 signaling in prostate cancer: CAF-driven immune evasion and therapeutic opportunities

Interleukin-6 (IL-6) plays a pivotal regulatory role in prostate cancer progression, contributing to therapy resistance and reshaping of the tumor microenvironment. This review outlines the clinical relevance of IL-6 as a potential prognostic biomarker and describes its mechanistic involvement in the development of castration resistance, with emphasis on its interplay with distinct cancer-associated fibroblast (CAF) subtypes. Elevated serum IL-6 levels in metastatic castration-resistant prostate cancer are associated with poor responses to docetaxel, enzalutamide, or abiraterone, and correlate with worse prognosis. Mechanistically, IL-6 promotes neuroendocrine differentiation and sustains cell survival under therapeutic stress through activation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and androgen receptor signaling pathways. Recent single-cell studies reveal that prostate CAFs are highly heterogeneous. Certain subtypes are linked to extracellular matrix remodeling and fibrosis, while others exhibit inflammatory or immune-modulatory characteristics, differentially influencing tumor evolution. Specific CAF subsets have been strongly implicated in promoting castration resistance and adverse outcomes. Therapeutic strategies targeting the IL-6/IL-6R axis-such as neutralizing antibodies, advanced chimeric antigen receptor (CAR)-T designs, and combination regimens-are under active investigation. Simultaneously, modulating CAF plasticity to convert tumor-promoting phenotypes into tumor-restraining ones represents a promising therapeutic avenue. A deeper understanding of IL-6 functions across CAF subtypes may unlock novel precision therapy opportunities for prostate cancer.