The lymphatic system in neurodegeneration, cancer, immunity, and metabolic disease: A unifying framework for disease pathogenesis and therapy

The lymphatic system is a fundamental regulator of tissue fluid balance, immune surveillance, antigen trafficking, lipid transport, macromolecular clearance, and inflammatory resolution across organ systems. Increasing evidence demonstrates that lymphatic dysfunction contributes directly to disease initiation and progression in a wide range of pathological states, including neurodegeneration, autoimmune disorders, chronic inflammatory diseases, metabolic syndromes, and cancer-related lymphedema. Across these conditions, impaired lymphatic transport may promote toxic protein accumulation, immune dysregulation, fibrosis, adipose remodeling, chronic inflammation, and failure of tissue repair.Lymphatic dysfunction is a major driver of morbidity, particularly following treatment for breast cancer, melanoma, gynecologic malignancies, genitourinary cancers (including prostate, bladder, penile, and testicular cancers), sarcoma, and head and neck cancers, where surgery, radiation, tumor invasion, and stromal remodeling may disrupt lymphatic integrity and drainage. The discovery of functional meningeal lymphatic vessels has fundamentally reshaped our understanding of central nervous system immunity and waste clearance, establishing the lymphatic system as a critical regulator of neuroimmune homeostasis. These vessels facilitate the clearance of macromolecules, immune mediators, and neurotoxic proteins from the brain, implicating lymphatic dysfunction as a potential contributor to neurodegenerative diseases such as Alzheimer’s disease. Beyond the central nervous system, lymphatic vessels play essential roles in immune surveillance, antigen trafficking, lipid transport, and inflammatory resolution. Emerging evidence demonstrates that lymphatic dysfunction contributes to the pathogenesis of autoimmune diseases, metabolic disorders such as diabetes and obesity, and chronic inflammatory conditions. Conversely, inflammatory and metabolic stress can directly impair lymphatic integrity and transport capacity. These bidirectional interactions position the lymphatic system as a central and previously underrecognized regulator of disease susceptibility, progression, and tissue homeostasis across organ systems. This Research Topic aims to define the lymphatic system as a central mechanistic link connecting neurodegeneration, cancer, immune dysregulation, chronic inflammation, and metabolic disease. We welcome original research, reviews, and perspectives that advance mechanistic, translational, or clinical understanding of lymphatic biology, dysfunction, imaging, and therapeutic modulation.Areas of interest include:• Lymphatic dysfunction in neurodegenerative diseases, including Alzheimer’s disease and related dementias• Lymphatic-mediated clearance of macromolecules, immune mediators, metabolites, and pathogenic proteins• Neuroimmune interactions and lymphatic regulation of central nervous system inflammation• Lymphatic dysfunction in autoimmune diseases, chronic inflammatory disorders, and systemic immune dysregulation• The role of lymphatics in metabolic disease, including diabetes, obesity, adipose inflammation, and insulin resistance• Cancer-related lymphatic dysfunction and lymphedema associated with breast cancer, melanoma, gynecologic malignancies, genitourinary cancers, sarcoma, and head and neck cancers• Tumor–lymphatic interactions, lymphatic remodeling in the tumor microenvironment, and treatment-associated lymphatic injury• Molecular mechanisms regulating lymphangiogenesis, lymphatic remodeling, fibrosis, immune trafficking, and transport function• Imaging, biomarkers, and quantitative assessment of lymphatic function in health and disease• Therapeutic approaches targeting lymphatic repair, enhancement of clearance, immune–lymphatic modulation, and prevention or treatment of cancer-related lymphedemaInterdisciplinary studies integrating neuroscience, oncology, immunology, metabolism, vascular biology, surgery, and translational therapeutics are particularly encouraged.The goal of this Research Topic is to establish lymphatic dysfunction as a central and potentially modifiable driver of neurodegeneration, oncologic morbidity, immune dysregulation, chronic inflammation, and metabolic disease. Recent discoveries have demonstrated that impaired lymphatic function may contribute directly to neurotoxic protein accumulation, chronic inflammation, fibrosis, adipose remodeling, tumor-associated stromal changes, and long-term treatment-related morbidity such as cancer-related lymphedema.These findings challenge traditional paradigms that view lymphatic impairment as a passive consequence of disease and instead suggest that lymphatic dysfunction may represent an upstream and unifying mechanism across diverse pathological conditions. Advances in imaging, molecular biology, surgical reconstruction, pharmacologic modulation, and regenerative lymphatic therapies now provide unprecedented opportunities to directly investigate and target lymphatic pathways.By integrating mechanistic, translational, and clinical research, this Research Topic seeks to advance a new framework in which the lymphatic system is recognized as a critical regulator of disease initiation, progression, and therapeutic response. This paradigm shift has the potential to enable the development of lymphatic-centered diagnostics and disease-modifying therapies across neurodegenerative, oncologic, autoimmune, inflammatory, and metabolic disorders.Dr. Stav Brown is a consultant to Impedimed. Dr. Jennifer Kwan declares financial grants from the University of Toronto and Princess Margaret Cancer Centre for research. Dr. Siba Haykal is a consultant to Stryker. All other Topic Editors declare no competing interests with regard to the Research Topic. Topic editors: Stav Brown, Siba Haykal, Felix J. Klimitz, MD, Jennifer Kwan, Mehra Golshan Source: https://www.frontiersin.org/research-topics/80258/the-lymphatic-system-in-neurodegeneration-cancer-immunity-and-metabolic-disease-a-unifying-framework-for-disease-pathogenesis-and-therapy