Abstract Nodal metastasis is the most common pattern of spread in head and neck squamous cell carcinoma (HNSCC). Nodal involvement has been linked to tumor aggressiveness and poor prognosis as reflected in the staging system. It also leads to the current surgical and radiation managements of HNSCC that include elective nodal treatment in addition to addressing gross disease. Yet, elective nodal treatment (either with surgery or radiation) has been linked to immune suppression since the tumor-draining lymph nodes (TDLN) are crucial for the development of a tumor-directed adaptive immune response, particularly in T-cell priming. Here I will touch on some recent work showing: (1) how nodal metastasis can influence tumor distant spread; (2) potential role of B cells in the TDLNs in driving anti-tumor T cell immunity through the recognition of extracellular vesicle-linked antigens, (3) potential treatment approaches of HNSCC that can mitigate the negative consequences of targeting TDLN. Citation Format: Quynh-Thu Le. Tumor draining lymph nodes: Friends or foes. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA03
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