The role of CCL22 and its histamine-associated modulation in the tumor microenvironment of tongue squamous cell carcinoma

Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)-expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor-immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22-CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.