Lymph node preservation as an immunotherapeutic catalyst

Lymph nodes are vital immunological organs, yet nodal surgery—including sentinel lymph node biopsy and completion lymph node dissection—is routinely performed in many solid tumors. Importantly, nodal surgery remains clinically valuable in selected settings, particularly for pathological staging and treatment decision-making, and in some contexts for regional disease control. We address a central paradox in surgical oncology: while lymph node dissection aims to control regional metastasis, emerging immunology suggests that intact tumor-draining regional lymph nodes can support antitumor immunity during immune checkpoint blockade. Although the immunological principles discussed may be relevant across a range of solid tumors, the most direct evidence to date comes from immunotherapy-treated settings—particularly tumor types with established checkpoint inhibitor activity—and from studies of regional, non-metastatic (tumor-draining) lymph nodes; whether these observations extend to immunotherapy-refractory tumors or metastatic nodes remains to be determined. Emerging evidence from preclinical models and correlative human studies suggests that tumor-infiltrating immune responses can be seeded from tumor-draining regional lymph nodes, supported by intratumoral tertiary lymphoid structures (ectopic lymphoid aggregates within tumors) and tumor-associated high endothelial venules (specialized venules that facilitate lymphocyte entry). With advances in imaging and drug-delivery platforms, even metastatic lymph nodes may also be addressed via non-surgical strategies. We propose the “Lymph Node Catalyst” hypothesis as an integrative, testable framework: preserved nodal-vascular circuits act as immunological reservoirs that may enhance responses to immunotherapy. This perspective reframes lymph nodes from solely metastatic waystations to context-dependent immune hubs in the immunotherapy era. Dual roles of lymph nodes in cancer. LNs enable DC-mediated priming and supply TLS/TME with effector and memory lymphocytes via HEVs, but metastatic editing of TDLNs (Treg/myeloid skewing, HEV injury) fosters immune escape and dissemination. The schematic emphasizes balancing node preservation against metastatic risk within multimodal care. Abbreviations: DC, dendritic cell; HEV, high endothelial venule; Treg, regulatory T cell.(Created with BioRender.) • Proposed the catalyst theory of lymph node preservation for the first time, shifting the perception of lymph nodes from conventional "risk reservoirs for metastasis" to "enhancers of immunotherapy". • Systematically reviewed the paradigm shift in lymph node management concepts in oncological surgery. • Elucidated the crucial roles of lymph nodes and tertiary lymphoid structures within the tumor immune microenvironment.