Advances in understanding the dual roles of testicular immune responses: From immune privilege to inflammation.

The testis is an immune-privileged organ that balances protection of developing germ cells with the need to respond to pathogens. This review summarizes the dual nature of testicular immunity. A tolerogenic microenvironment is maintained through the blood-testis barrier (BTB) and immunomodulatory factors from Sertoli and Leydig cells, which suppress immune activation and preserve spermatogenesis. When infection, inflammation, or environmental stress disrupts this balance, immune responses shift toward pathology, inducing inflammatory cascades, apoptosis, and impaired fertility. We highlight the tightly regulated complement system, the plasticity and crosstalk of testicular immune cells-including macrophages, dendritic cells (DCs), T cells, and B cells-and the central role of the Toll-like receptor (TLR)-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome-Reactive oxygen species (ROS) axis in mediating inflammation and cell death. Viral infections further induce remodeling of the BTB, perturb immune homeostasis, and contribute to the development of orchitis. Overall, testicular immunity exhibits both protective and pathogenic features, offering insights for targeted therapies in male reproductive immune disorders.