Immune microenvironmental patterns in rapidly progressive young-onset tongue cancer: A case series analysis

Young-onset tongue cancer is increasingly recognized as a distinct clinical entity, differing from conventional tongue cancer associated with alcohol and tobacco use in terms of risk factors, clinical behavior, and molecular alterations. In rapidly progressive cases, delayed diagnosis and therapeutic challenges have been highlighted. Prior studies have implicated a myeloid-inflamed tumor microenvironment in this subset, suggesting that unique immune landscapes may influence diseases trajectories and treatment response. We analyzed five cases of rapidly progressive young-onset tongue cancer, focusing on clinical characteristics, genetic alterations, and immune tumor microenvironmental features assessed by 14-marker multiplex immunohistochemistry. Patients ranged from 22 to 48 years (median, 40 years), with a median time to recurrence of three months following initial treatment. Three of 5 patients had no history of alcohol or tobacco use. TERT promoter mutation were identified in two cases. All tumors exhibited abundant tumor-associated macrophages. CD8 + T cell infiltration showed inter-case variability, ranging from sparse to dense. However, in contrast to non-young-onset tongue cancer tissues, CD8 + T cells in young-onset cases were frequently excluded from tumor cell nests, even in specimens with high overall infiltration. These findings suggest the presence of immune exclusion mechanisms underlying the rapid progression of young-onset tongue cancer. Immune exclusion may represent a key barrier to effective immunotherapy in this population and warrants further investigation as a therapeutic target.