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Tumor-draining lymph nodes play a paradoxical role in cancer. Surgeons often resect these sentinel lymph nodes to determine metastatic spread, thereby enabling prognosis and treatment. However, lymph nodes are vital organs for the orchestration of immune responses, due to the close encounters of dedicated immune cells. In view of the success of immunotherapy, the removal of tumor-draining lymph nodes needs to be re-evaluated and viewed in a different light. Recently, an important role for tumor-draining lymph nodes has been proposed in the immunotherapy of cancer. This new insight can change the use of immune checkpoint therapy, particularly with respect to the use in neoadjuvant settings in which lymph nodes are still operational.