Cytokine symphony: Deciphering the tumor microenvironment and metastatic axis in oral cancer.

Oral cancer remains one of the deadliest diseases due to its aggressive nature, high metastatic potential, and limited therapeutic success. The tumor microenvironment (TME) serves as a central regulator in the metastasis of oral cancer by shaping tumor-stroma interactions, immune modulation, and metastatic dissemination. Among the key regulators of the TME, cytokines act as one of the molecular orchestrators, mediating inflammation, immune suppression, epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. This review explores the regulatory networks driven by cytokines from TME that govern tumor metastasis in oral cancer. Pro-tumorigenic cytokines such as IL-6, IL-8, TGF-β, TNF-α, etc., drive EMT, extracellular matrix (ECM) remodeling, and immune evasion, facilitating tumor invasion and metastatic colonization. Conversely, anti-tumor cytokines, including IFN-γ, IL-12, etc., play a role in immune activation but are often downregulated in the immunosuppressive TME. Additionally, the complex crosstalk between immune cells, tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) further amplifies cytokine-driven tumor metastasis. Understanding the "cytokine symphony" that governs oral cancer progression and metastasis is critical for developing targeted therapies. Here, we discuss the cytokine crosstalk in TME and its implication in metastasis and conclude with an emerging cytokine-targeting strategy, including anti-IL-6/STAT3 inhibitors, IL-8 blockade, and immune checkpoint inhibitors, as potential approaches to modulate the TME and suppress oral cancer metastasis. Future clinical studies are essential to validate cytokine-based interventions and pave the way for precision medicine in oral cancer management.