<p>Metastatic lesions in cervical lymph nodes are generally less sensitive to induction chemotherapy than primary tumors, making cervical lymph node metastasis one of the most significant prognostic factors in head and neck squamous cell carcinoma (HNSCC). However, the underlying mechanism of cisplatin resistance in these lymph nodes remains unclear. Lipidomic analysis of 21 HNSCC patients revealed distinct lipid profiles between cervical lymph node metastases and primary tumors, with triglycerides notably enriched in the metastatic nodes, suggesting a critical role for adipocytes. Further investigation confirmed the presence of cancer-associated adipocytes within cervical lymph node metastases, which supply triglycerides to tumor cells. The hypoxic tumor microenvironment promotes apoptosis and necrosis in adipocytes, a process accelerated by hypoxic tumor cells, leading to increased triglyceride release. In HNSCC cells, triglycerides promote lipid droplet accumulation and enhance contact between lipid droplets and mitochondria via the interaction of perilipin-2 (PLIN2) and carnitine palmitoyltransferase-1A (CPT1A), thereby reversing cisplatin-induced rises in intracellular reactive oxygen species (ROS). In vivo, xenograft tumors located in adipocyte-rich regions showed larger volume and greater mass after cisplatin treatment. This study is the first to demonstrate that adipocytes are key components in cervical lymph node metastasis of HNSCC and are closely associated with cisplatin resistance. Mechanistically, the hypoxic tumor microenvironment facilitates crosstalk between tumor cells and adipocytes, increasing triglyceride supply from adipocytes. This, in turn, promotes lipid droplet–mitochondria contact in HNSCC cells through PLIN2–CPT1A binding, counteracting cisplatin-induced ROS elevation and contributing to chemoresistance</p>