The pivotal role of tumor-draining lymph nodes (TDLNs) in supporting antitumor immunity and serving as sites for cancer metastasis presents a clinical challenge: eliminate tumors while preserving antitumor immune responses. In this article, we explore the initiation of tumor-specific immune responses within lymph nodes (LNs), the immunocompromised microenvironment induced by tumors within LNs, and the crucial involvement of TDLNs in immunotherapy. Additionally, we examine the clinical prospects of modifying surgical procedures or therapy sequences to enhance the efficacy of cancer treatment.