Immunological mechanisms and precision stratification in male infertility: from testicular immune privilege and danger signal amplification to seminal immune biomarkers and mechanism-tailored intervention

Male infertility presents significant heterogeneity, yet traditional assessments primarily rely on semen parameters and endocrine, imaging, and genetic screening. Although these methods can identify some definitive etiologies, a mechanistic explanatory gap persists in large populations with mild to moderate oligoasthenoteratozoospermia, elevated sperm DNA fragmentation, or recurrent adverse reproductive outcomes. The testis maintains a dynamic immune-privileged balance by balancing infection defense against tolerance to post-pubertal germ cell antigens. In this context, infections, varicocele-induced hypoxia or thermal stress, metabolic abnormalities, and environmental factors, trigger innate immune recognition via PAMPs or DAMPs. Notably, most mechanistic insights discussed are derived from animal models and in vitro studies; direct high-level clinical evidence in humans remains limited, and the proposed framework requires prospective validation. This is proposed to drive myeloid amplification, complement cascades, and inflammasome activation, which may in turn mutually reinforce oxidative stress. Based on current evidence, this may consequently compromise blood-testis barrier integrity, cause immune tolerance thresholds to decline, and induce tissue remodeling, collectively impairing the spermatogenic microenvironment, sperm maturation, and DNA integrity. This article reviews these immunological mechanisms and proposes a hypothesis-driven intervention framework driven by immune endophenotypes, aiming to provide an actionable clinical roadmap for the precision management of male infertility.