Nerves, Nodes, and Neoplasia

Minjun Wang¹Censhan Ran²Quan Liu^1*

• ¹Southern University of Science and Technology, Shenzhen, China
• ²Shanghai Jiao Tong University School of Medicine, Shanghai, China

Tumor immune evasion and incomplete responses to immunotherapy are some of the greatest most significant obstacles in current cancer treatment. Since tumor-draining LNs (tdLNs) are cradles for anti-tumor immunity, and tumor-specific memory cells in tdLNs are the bona fide responders to immune-checkpoint blockade, tdLNs are increasingly valued in oncoimmunology research and cancer treatments. Recent progress has revealed that lymph nodes (LNs) are innervated and regulated by sensory and sympathetic nerve fibers. Because tumor cells, nerves, and immune cells coexist inside tdLNs—sites where anti-tumor immunity is both initiated and compromised—a comprehensive understanding of tumor-neuro-immune crosstalk within LNs is essential for understanding the mechanisms of immune evasion and advancing tumor surgical and immunological therapies. it is critical to investigate whether tumor-neuro-immune crosstalk also occurs in these nodes. Although direct evidence in tdLNs is lacking, we synthesize emerging evidence supporting this possibility. We argue that validating this hypothesis will be essential for elucidating immune evasion mechanisms and advancing surgical and immunological strategies against tumors. In this review, we first introduce LN anatomy, highlighting their its innervation by sensory and sympathetic fibers. We then examine in depth the neural regulation of immune activities, especially those within LNs and those associated with a tumor context. We further discuss in detail the multifaceted roles of tdLNs in tumor immunology, including orchestration of anti-tumor immunity and local immunosuppression, pre-metastatic LN remodeling, and induction of systemic tumor-specific immune tolerance. Furthermore, we look into tumor-neural interactions from 2 two angles: tumor-induced nerve growth and activation; , and neural regulation of tumor growthprogression. Finally, we propose potential tumor-neuro-immune interactions in tdLNs, and discuss current perspectives on LN handling in cancer therapy, together withdiscuss current perspectives on LN handling in cancer therapy, and discuss clinical implications of the progress summarized in this review.