Abstract A062: Endometriosis as a Neuroimmune Disorder: Integrating Inflammation, Innervation, and Sensitization

Abstract Endometriosis (EMS) is an estrogen-dependent, chronic inflammatory disease in which endometrial-like tissue grows outside the uterus, leading to pelvic pain, dysmenorrhea, dyspareunia, and infertility. Increasing evidence shows that these symptoms do not arise from the presence of ectopic tissue alone. Rather, they reflect a sustained neuroimmune process in which inflammatory, neural, and stromal pathways continuously interact. Within the peritoneal cavity of EMS, immune activation elevates cytokines such as IL-1β, IL-6, and TNF-α, which stimulate production of neurotrophic mediators including NGF, BDNF, and IGF-1. These signals induce sensory-nerve sprouting, lower nociceptor thresholds, and convert lesions into hyperinnervated, pain-generating structures. Once these fibers infiltrate lesions, they release neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP). Rather than simply transmitting nociceptive signals, these neurons actively reshape the lesion microenvironment. SP and CGRP amplify inflammation, promote immune-cell recruitment, and drive epithelial–mesenchymal transition and myofibroblast differentiation, accelerating the fibrotic remodeling characteristic of deep infiltrating endometriosis. This neuropeptide-driven activity strengthens the lesion’s neuroimmune profile and forms a feed-forward loop in which inflammation, nerve growth, and fibrosis reinforce one another over time. Persistent nociceptive input from sensitized lesions produces downstream changes in the central nervous system. Within the spinal cord, activated microglia and astrocytes release proinflammatory mediators that enhance excitatory signaling and diminish inhibitory tone. With continued input, spinal and cortical circuits undergo neuroplastic changes that give rise to central sensitization, hyperalgesia, allodynia, and the cross-organ sensitization that links pain across the uterus, bladder, bowel, and pelvic floor. These long-range effects explain why pain may persist even when visible lesions are small or surgically removed. Together, these findings position endometriosis as a chronic systemic neuroimmune disorder maintained by reciprocal signaling between immune cells, sensory neurons, and central pain networks. Viewing EMS through this lens highlights multiple therapeutic entry points. Targeting NGF–TrkA and CGRP–RAMP1 signaling, modulating macrophage and B-cell function, dampening glial activation, or applying neuromodulatory techniques offers a more rational pathway to interrupt the self-reinforcing neuroimmune loop that sustains pain. Integrating immunologic and neurobiologic evidence therefore provides a foundation for mechanism-based therapies capable of delivering more durable relief and improving long-term quality of life. Citation Format: Ariana F. Rahman. Endometriosis as a Neuroimmune Disorder: Integrating Inflammation, Innervation, and Sensitization [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A062.