Platelet-driven immunothrombotic remodeling programs convert ectopic endometrium into fibrotic, immune-privileged lesions.

Endometriosis is a chronic, heterogenous disorder in which cyclical hemorrhage and repetitive repair generate ectopic implants that persist, recur, and drive pain and infertility; conventional frameworks emphasizing hormonal aberration and immune failure incompletely explain lesion fibrotic maturation and spatial heterogeneity. We synthesize human, experimental, and emerging spatial-omic evidence to advance a unifying mechanistic paradigm: cyclical bleeding seeds an immunothrombotic niche in which activated platelets and fibrin scaffolds organize immune cells and stromal responders, and platelet-derived signals, including P-selectin, TGF-β and platelet-derived microparticles (PMPs), act as upstream instructors of both immune dysregulation and fibrogenic stromal reprogramming. Quantitative histology and SHG imaging demonstrate spatial platelet hotspots that co-localize with NK suppression, CD163+ macrophage polarization and aligned collagen bundles in human lesions, while PMP proteomics and functional uptake assays link vesicular cargo to myofibroblast and reparative macrophage transcriptional programs. Mechanistically, platelet TGF-β and PMP cargo downregulate NK effector receptors (for example NKG2D), reprogram macrophages toward LOX-enriched matrix-remodeling states, and bias adaptive responses toward tolerance (Treg/Th17 imbalance), creating microdomains permissive for lesion survival. These processes engage a mechanobiological feedback loop: LOX-dependent collagen crosslinking increases stiffness, which amplifies myofibroblast and immune phenotypes and further recruits platelets, consolidating fibrotic architecture. We propose a research and translational roadmap, standardized PMP pipelines, integrated scRNA/spatial cohorts, ex vivo perturbations, and early proof-of-concept trials targeting adhesion (P-selectin), PMP biology, TGF-β activation or LOX, to test causality and enable precision interventions for the "immunofibrotic" endometriosis phenotype. Reframing endometriosis as a platelet-organized immunofibrotic disorder identifies novel druggable nodes and biomarker strategies with immediate potential to change both mechanistic research and clinical management.