Adipokine regulation of immune cell polarization in oral cancer and its impact on chemotherapy sensitivity

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region. In locally advanced patients, neoadjuvant chemotherapy centered on cisplatin and 5-fluorouracil often leads to primary/acquired resistance, with a 5-year survival rate of less than 50%. Tumor microenvironment (TME) immunosuppressive remodeling is the core cause of chemotherapy failure. Adipokines secreted by cancer-associated adipocytes (CAAs) are the key mediators that link metabolic disorders, immune polarization and chemotherapy resistance. The adipokines leptin, adiponectin, chemerin, resistin, and GDF15 signal through pathways such as JAK2/STAT3, PI3K/AKT, NF-κB, and PPARγ to bidirectionally regulate the polarization phenotypes of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), CD4 + /CD8 + T cells, and NK cells. Pro-cancer adipokines induce M2-type TAMs, MDSCs expansion, Th2/Th17 polarization, and effector T cell exhaustion, constructing an immunosuppressive microenvironment, upregulating DNA damage repair, drug efflux, and anti-apoptotic genes, and reducing cisplatin/5-FU chemosensitivity. The tumor-suppressive adipokine adiponectin promotes M1 macrophage and CD8 + effector T cell infiltration, reverses immunosuppression, and sensitizes chemotherapy. This article systematically reviews the origin and classification of adipokines, the polarization patterns of immune cells in the OSCC microenvironment, the molecular pathways by which various adipokines regulate immune polarization, and the complete mechanism by which immune polarization mediates chemotherapy resistance. It summarizes the value of clinical markers and targeted reversal strategies, points out current research bottlenecks, and looks forward to the translational prospects of metabolism-immunotherapy combined with chemotherapy, aiming to provide new metabolism-immune targets for overcoming chemotherapy resistance in oral cancer.