Immunosuppression as a hypothesized central pathological hub in andrological diseases: a hypothesis-generating framework

Male reproductive health disorders-including chronic prostatitis (CP), infertility, and genitourinary malignancies-are increasingly understood as resulting from sustained immune imbalance. While physiological immunosuppression is essential for maintaining immune privilege and reproductive function, its pathological dysregulation is an underestimated contributor to disease. Moving beyond the traditional view of immunosuppression as a mere bystander, this framework proposes it as a common and actionable hypothesized central pathological hub across the spectrum of andrological diseases. We synthesize evidence for how dysregulated immunosuppressive networks-including expanded regulatory T cells(Tregs), activated checkpoint pathways, immunometabolic reprogramming, and epigenetic modifications-shift from maintaining protective homeostasis to promoting chronic inflammation, tissue fibrosis, and tumor immune evasion. Importantly, this unified framework uncovers shared mechanistic foundations that connect inflammatory, dysfunctional, and neoplastic conditions of the male reproductive tract. From a translational perspective, we highlight emerging immunotherapeutic strategies-such as checkpoint inhibitors, metabolic modulators, and epigenetic drugs-that target this central hub. By reconceptualizing immunosuppression as a hypothesized central pathological hub, this framework suggests that (1) the transition from physiological protection to pathological promotion may be driven by chronic metabolic and epigenetic reprogramming; (2) shared checkpoint, metabolic, and cellular mechanisms may operate across CP/CPPS, male infertility, and genitourinary malignancies; and (3) therapeutic recalibration without disrupting testicular privilege may be achievable in principle, but remains unproven. This framework is proposed as a testable hypothesis, not a concluded model.