Testicular macrophages: core immune regulators and emerging therapeutic targets in spermatogenic dysfunction

Spermatogenic dysfunction is one of the leading causes of male infertility, mainly including non-obstructive azoospermia (NOA) and abnormalities in sperm count or quality. As an immune-privileged organ, the testis relies heavily on immune homeostasis to sustain spermatogenesis, with testicular macrophages playing a central regulatory role in this process. Under normal physiological conditions, testicular macrophages predominantly exhibit immune tolerance-related phenotypes, regulate local inflammatory responses, maintain immune privilege, and contribute to hormonal homeostasis, all of which collectively support spermatogenesis. However, during spermatogenic dysfunction, significant alterations occur in the number, distribution, functional status, and signaling pathways of testicular macrophages. Aberrant activation of inflammation-related signaling pathways in macrophages and imbalance in immune regulation can induce chronic low-grade inflammation, disrupt the spermatogenic microenvironment, and further exacerbate spermatogenic dysfunction. In recent years, with the advancement of reproductive immunology and single-cell RNA sequencing technologies, numerous studies have highlighted the critical role of testicular macrophages in spermatogenic dysfunction and explored potential therapeutic strategies targeting these cells. Nevertheless, the existing body of research is fragmented, lacking systematic reviews and comprehensive integration. This review aims to provide a comprehensive synthesis of the developmental origins and functional heterogeneity of testicular macrophages and to discuss their mechanistic roles in various male spermatogenic dysfunctions. Furthermore, we review the current therapeutic advances targeting testicular macrophages and discuss the main challenges and future research directions in this field. Our study provides theoretical insights for the mechanistic study of male spermatogenic dysfunction and the development of precision intervention strategies.