From clinical observations to molecular insights: Decoding immune checkpoint inhibitors-induced prostatitis

Immune checkpoint inhibitors (ICIs) have dramatically transformed cancer treatment; however, their impact on the male reproductive system remains poorly understood. This study aims to elucidate the incidence, risk factors, and molecular mechanisms underlying ICI-associated prostatitis. We conducted an analysis of ICI-associated prostatitis utilizing the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database and evaluated risk through the application of the reporting odds ratio. A mouse model of ICI treatment was developed, and subsequent transcriptomic changes in prostate tissue were investigated using high-throughput sequencing. Hematoxylin and eosin staining, immunohistochemistry, Von Frey testing, and enzyme-linked immunosorbent assay were employed to confirm ICI-induced prostatitis and further delineate its underlying mechanisms. Additionally, we investigated the therapeutic potential of specifically targeting interleukin-6 (IL-6) and extracellular signal-regulated kinase (ERK) signaling pathways. FAERS analysis demonstrated a statistically significant positive correlation between ICI treatment and prostatitis risk (p < .05). In the murine model, ICI treatment induced an elevated inflammatory response in prostate tissue, characterized by enhanced inflammatory cell infiltration and upregulated expression of IL-6 and tumor necrosis factor-alpha. Transcriptomic analysis revealed significant activation of multiple inflammation-related signaling pathways in prostate tissue following ICI treatment (false discovery rate < 0.05). Targeted inhibition of IL-6 or ERK signaling pathways significantly attenuated ICI-induced prostatitis symptoms, resulting in improved tissue pathology and decreased inflammatory factor expression (p < .01). This study delineates the characteristics and potential molecular mechanisms underlying ICI-associated prostatitis, thereby establishing a theoretical foundation for the development of prevention and treatment strategies. Targeted modulation of IL-6 and ERK signaling pathways may present novel therapeutic interventions for ICI-associated prostatitis, thus warranting further clinical validation.