Chemokines and Their Receptors in Oral Squamous Cell Carcinoma: Mechanisms, Clinical Significance, and Therapeutic Implications

Dandan LiShuangshuang ChenJiahao JiZhenwu WangHan ZhouZiyi LiaoQun Tang^*

• Hunan University of Chinese Medicine, Changsha, China

Chemokines, a category of cytokines exhibiting chemotactic properties, have been thoroughly investigated as targets in cancer treatment in recent decades. In oral squamous cell carcinoma (OSCC), a prevalent and high-risk malignancy of the head and neck, chemokines interact with their specific receptors to initiate downstream signaling pathways. This signaling influences not only tumor cell proliferation, migration, invasion, and metastasis of oral cancer cells but also angiogenesis and vascular maturation. Furthermore, they modulate the tumor microenvironment (TME), which consists of diverse cellular and molecular components that collectively create a permissive niche for tumor growth, metastasis, and therapeutic resistance. This modulation impacts the recruitment and functionality of immune cells, which in turn influences tumor immune evasion and immune surveillance. Various chemokines and their receptors have distinct expression patterns in oral cancer tissues compared to normal tissues. Certain chemokines may function as prospective diagnostic markers, prognostic indicators, and therapeutic targets. In this review, we systematically summarize research advancements on chemokines in OSCC, elucidating their molecular mechanisms in tumor initiation and progression with a focus on the dualistic roles of key chemokine families (e.g., CCL2/5/20/19/21, CXCL1/8/12, CX3CL1) in regulating immune responses, tumor-stroma interactions, vascular remodeling, and chemotherapy resistance. We also recap current chemokine/receptor-targeted therapeutic strategies and discuss the limitations of existing research, including incomplete mechanistic understanding of understudied chemokine subfamilies (beyond CXC and CC subfamilies) and limited clinical translation of chemokine-based diagnostics and therapeutics. Finally, we propose future research directions: prioritizing patient stratification based on chemokine profiles, developing targeted delivery systems for chemokine antagonists, and combining these approaches with emerging therapies to overcome treatment resistance. This review underscores the critical role of chemokines in OSCC biology and their promising potential to guide the development of novel, effective therapeutic interventions.