Endometriosis Immunopathology: The Macrophage Connection

How Macrophages and Extracellular Vesicles Shape the Immune Landscape of Endometriosis?

Key Points

Highlights:

• Macrophages and extracellular vesicles (EVs) are central players in shaping the immune microenvironment of endometriosis.
• Their interaction promotes lesion survival, angiogenesis, and immune evasion, but also reveals novel therapeutic entry points.

Importance:

• Understanding how macrophage plasticity and EV signaling contribute to disease progression may uncover new biomarkers and therapeutic strategies for endometriosis, moving beyond traditional hormonal approaches.

What's Done Here?

• This review synthesizes recent evidence on the dual role of macrophages—ranging from pro-inflammatory (M1) to pro-repair (M2)—and their reprogramming by endometriotic lesions.
• It explores how EVs mediate communication between immune, stromal, and endothelial cells, sustaining inflammation and fibrosis.
• The authors highlight translational opportunities, including macrophage reprogramming therapies, EV-based biomarkers, and drug delivery systems targeting the immune niche.

Key Findings:

• Endometriotic lesions release EVs carrying microRNAs and proteins that skew macrophages toward an M2-like, pro-endometriotic phenotype.
• These macrophages in turn support lesion growth via angiogenesis, extracellular matrix remodeling, and suppression of cytotoxic immune responses.
• EVs may serve as stable, minimally invasive biomarkers detectable in serum, urine, or menstrual effluent.
• Therapeutic interventions aimed at modifying macrophage polarization or intercepting EV signaling are under active investigation, with promising preclinical results.

Strengths and Limitations:

• Study provides a mechanistic, immunology-focused synthesis that integrates both macrophage biology and EV dynamics; which are strengths.
• Limitations are; evidence remains largely preclinical, with limited patient-derived validation; Clinical feasibility of EV-based diagnostics and macrophage-targeting therapies still requires rigorous testing in large-scale trials.

From the Editor-in-Chief – EndoNews

"This review highlights an underappreciated truth: endometriosis is not only a hormonal disease but also an immune-driven disorder. By showing how macrophages and extracellular vesicles (EVs) orchestrate inflammation, angiogenesis, and fibrosis, the authors illuminate a critical dimension of pathogenesis that has therapeutic implications.

What makes this work important is the dual perspective it offers. On one hand, macrophage–EV interactions explain why lesions escape immune clearance and remodel their microenvironment. On the other, these same mechanisms open promising doors for innovation: EVs as circulating biomarkers for earlier, noninvasive detection, and macrophage reprogramming or EV-blockade as future treatment strategies.

The field must now move beyond descriptive immunology to functional translation. Carefully designed clinical studies—integrating immunology, gynecology, and bioengineering—will be essential to validate these mechanisms and bring macrophage- and EV-based diagnostics or therapies into clinical practice.

This review rightly emphasizes that the immune landscape of endometriosis is modifiable. Targeting it could transform both diagnosis and management."

Lay Summary

Macrophages and tiny signaling particles called extracellular vesicles (EVs) are emerging as central immune players in how endometriosis develops and persists.

Together, they shape the immune environment around endometriotic lesions, helping them survive, spread, and resist the body’s defenses.

In a recent review published in the Journal of Ovarian Research, Dr. Azari-Dolatabad from the Department of Biology, Science and Research from Islamic Azad University, Tehran-Iran, and colleagues from Belgium and USA, bring together the latest findings on the crosstalk between macrophages, EVs, and other cells in endometriosis.

The authors show how EVs can carry microRNAs and proteins that “reprogram” macrophages into a form that supports blood vessel growth, suppresses immune attack, and promotes scar tissue formation.

The review also emphasizes translational opportunities. EVs, which are stable and detectable in blood, urine, or menstrual effluent, could serve as noninvasive biomarkers of endometriosis.

Therapeutic strategies under investigation include reprogramming macrophages to restore immune balance or blocking EV-mediated signaling to halt lesion progression.

While much of the evidence is still preclinical, this work highlights how rethinking the immune landscape of endometriosis could open new paths for earlier diagnosis and novel treatments beyond hormones or surgery.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40481352/