Positive human papillomavirus (HPV +) head and neck squamous cell carcinoma (HNSCC) presents a higher risk of lymph node metastasis and poor prognosis. Here, advanced microarray analysis of clini-cally collected HNSCC tissues revealed significant upregulation of the lncRNA SELL in HPV+ HNSCC, and its overexpression was obviously associated with lymph node metastasis. The lncRNA SELL could func-tion as a promigratory and proinvasive mediator as well as an inducer of M1-like tumour-associated macrophages (TAM) by increasing the level of L-selectin. Furthermore, fucoidan, as an L-selectin inhibitor, obviously weakened the formation of tongue lesions induced by 4-Nitroquinoline N-oxide (4-NQO) in HPV16 E6/E7 transgenic mice. This result drove us to synchronously develop a nanodelivery platform to verify fucoidan-mediated anti-growth and anti-metastasis effects. This work highlighted the important influence of the lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposed a potential fucoidan-mediated therapeutic strategy.Statement of significance Head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV) involvement present a greater risk of lymph node metastasis than HPV negative HNSCC patients. However, treatment protocols, including surgery and platinum-based chemo-and radiotherapy, have not improved the 5-year overall survival due to the high tendency of lymphatic metastasis. Here, microarray of clinical HNSCC samples confirms the oncogenic significance of lncRNA SELL, which acts as an M1-like TAM inducer and promotes tumorigenesis by upregulating L-selectin. Fucoidan, as an L-selectin inhibitor, suppresses tongue lesions in transgenic mice, and a fucoidan-mediated nanodelivery platform inhibits HPV+ HNSCC growth. The present study highlights lncRNA SELL/L-selectin on promoting HPV+ HNSCC progression and proposes a potential fucoidan-mediated therapeutic.& COPY; 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.