Volume 172, 1 March 2026, 116242Author links open overlay panelShuang Wu a 1, Dashuai Miao c 1, Jinling Chen b, Wenliang Ge aShow moreHighlights•

Reveals the central role of testicular macrophages in testicular development and disease.

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Elucidates the origin and heterogeneity of testicular macrophages and their specific mechanisms in immune regulation.

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Analyses the role of macrophages and potential therapeutic pathways in diseases such as cryptorchidism.

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Proposes a novel immunotherapy strategy based on macrophage polarization.

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Proposes a multi-target regulation strategy by combining traditional Chinese medicine with modern immunology.

Abstract

Testicular development is a complex biological process that relies on three critical elements: proper anatomical development of the reproductive system, precise hormonal regulation, and coordinated interactions among various cell populations sustaining a functional micro-environment within the testis. The testicular immune micro-environment is essential for normal testicular development. As principal regulatory components of this specialized niche, testicular macrophages demonstrate remarkable functional and phenotypic diversity, serving as critical mediators of immune homeostasis within the testis. Immune signaling molecules associated with macrophages shape the immune landscape of testicular diseases through signal transduction and transcriptional and post-transcriptional mechanisms. Based on a specific account of the function of testicular macrophages on the testis and signaling molecular exchanges between the various cells, this review reveals the pathogenic mechanisms of testicular macrophages in a range of testicular developmental diseases. It provides suggestions for the design of new immunotherapies.

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Access through your organizationSection snippetsBackground

Global epidemiological data indicates that infertility affects approximately 12.6%–17.5% of reproductive-aged individuals worldwide [1], with abnormal testicular development being a major contributor to male infertility [2]. Testicular developmental diseases not only directly impair spermatogenic processes but are strongly associated with systemic health issues, such as metabolic syndrome, as well as psychosocial burdens. Established during embryonic development and refined during puberty,

Testicular macrophages: origin and development

The unique composition of the testicular immune micro-environment is closely linked to the process of spermatogenesis. TMs, as key members of the tissue-resident macrophage population, play a vital role in maintaining spermatogenic homeostasis by regulating the local immune response and promoting the function of Leydig cells. Not only do these cells possess the self-renewal capacity of embryonic origin, but dynamic changes in their phenotype and function are also directly linked to the

Functional characteristics of testicular macrophages

Macrophages are well-established as key immune cells with essential roles in both innate and adaptive immunity. Within the testis, they exhibit remarkable functional diversity [17], [19], [20], [22] throughout development and adulthood (Fig. 2, Fig. 3).

Cryptorchidism

Testicular descent is a critical milestone in male reproductive development, ensuring that the testes move into the scrotum, where cooler temperatures are vital for normal sperm production. This process occurs in two distinct phases. In the early transabdominal phase, insulin-like factor 3 (INSL3), a peptide hormone produced by fetal Leydig cells, promotes growth and swelling of the gubernacular region and positions the testes close to the future inguinal canal [76], [77]. After a transient

Macrophages as a starting point for the treatment of testicular diseases

Macrophages exhibit remarkable plasticity, dynamically adjusting their phenotype in response to tissue-specific cues and environmental stimuli. This functional heterogeneity has led to the identification of distinct macrophage subpopulations, each playing a key role in disease pathogenesis and offering potential therapeutic targets. Researchers identified the localization of EphB4 and ephrin-B1 in TMs, along with EphB4 tyrosine phosphorylation. This suggests that the EphB4/ephrin-B1 signaling

Conclusions

In recent years, significant progress has been made in the study of the mechanism of action of TMs in testicular development and diseases. As the core regulator of the testicular immune micro-environment, macrophage dysfunction is closely related to testicular diseases and has the potential for targeted therapy. The above review systematically summarizes the specific research progress of recent literature on macrophage related mechanisms and targeted therapies. Although existing research has

Authors' contribution

Shuang Wu drafted the manuscript. Dashan Miao critically revised and polished the content. Jinling Chen supervised the review process and quality control. Wenliang Ge conceptualized the review framework and established the research vision. All authors read and approved the final manuscript.

CRediT authorship contribution statement

Shuang Wu: Writing – original draft. Dashuai Miao: Writing – review & editing. Jinling Chen: Supervision. Wenliang Ge: Funding acquisition.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

This review was supported by the National Natural Science Foundation of China (No.82471631).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

Not applicable.

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These authors contributed equally to this work

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