Neuroimmune fitness in endometriosis: decoding the adaptive neural circuits that sustain lesion persistence, fibrosis, and chronic pain.

Endometriosis is a chronic inflammatory disease characterized by substantial heterogeneity in pain, lesion behavior, and treatment response. Although hormonal and surgical therapies can reduce disease activity and symptoms, their effects are variable, and the biological mechanisms underlying persistent pain and lesion recurrence remain incompletely understood. Emerging evidence supports reciprocal interactions among sensory neurons, immune cells, stromal populations, the vasculature, and the extracellular matrix in endometriotic lesions. Rather than proposing these interactions as a new observation, we use them as the biological basis for a testable Neuroimmune Fitness Landscape, in which lesion persistence is hypothesized to reflect the capacity of the local microenvironment to maintain coordinated neural, immune, stromal, vascular, and metabolic activity despite defined perturbations. We further propose that this framework may help organize established mechanisms underlying pain heterogeneity, tissue remodeling, lesion persistence, and therapeutic response, while generating experimentally testable predictions regarding network persistence, resilience, and reversibility. Importantly, the framework is conceptual and does not establish neuroimmune fitness or neuroimmune memory as validated biological entities. We discuss how this model could guide future studies of neuroimmune modulation, metabolic intervention, targeted delivery, and precision phenotyping. We also identify neuroimmune memory as a distinct, unresolved hypothesis that would require longitudinal demonstration of persistence, enhanced responses to subsequent challenge, and reversibility after targeted intervention. Thus, the proposed framework should be viewed as a hypothesis-generating model for integrating existing evidence and directing experimental validation, rather than as an established explanation of endometriosis persistence or therapeutic resistance.