Mechanobiological and microenvironmental roles of lymph nodes in cancer: implications for lymph node de-escalation.

Prophylactic lymph node (LN) dissection has long been regarded as an important component of surgical treatment for many solid tumors, based largely on the traditional anatomical view that LNs serve as "relay stations" for tumor metastasis. However, recent clinical studies in melanoma, breast cancer, and other malignancies have increasingly suggested that, in patients with clinically negative or low-burden positive LNs, routine extensive LN dissection does not always translate into a clear overall survival benefit and may instead increase complications such as lymphedema and neurovascular injury. In parallel, advances in tumor mechanobiology have provided a new theoretical framework for reinterpreting lymphatic metastasis and LN management strategies. Increased extracellular matrix stiffness, accumulation of solid stress, and elevated interstitial fluid pressure within the tumor microenvironment (TME) together constitute a coupled solid stress-fluid stress system. This system not only promotes tumor cell invasion, lymphangiogenesis, and directed migration toward the lymphatic system, but also regulates the functions of dendritic cells, macrophages, lymphatic endothelial cells (LEC), and T cells, thereby driving the formation of an immunosuppressive premetastatic niche in tumor-draining LNs (TDLNs). From this perspective, LNs should be understood not merely as anatomical structures, but as functional hubs of tumor-immune-mechanical interaction. Based on current evidence from melanoma, breast cancer, head and neck squamous cell carcinoma, lung cancer, and gastrointestinal malignancies, this article discusses the theoretical basis, applicable boundaries, and translational significance of LN de-escalation strategies, and reviews the dual role of TDLNs in metastasis and antitumor immunity from the intersecting perspectives of tumor biomechanics, lymphatic biology, and tumor immunology. We propose that LN management should shift from a traditional anatomy-oriented approach to a function-oriented precision strategy, thereby providing a new theoretical basis for future cancer treatment.