Diagnostics · Oct 23, 2026
The Immune-Senescent Switch in Oral Carcinogenesis: From Premalignancy to Malignant Transformation—Does Periodontitis Tip the Balance? A Hypothesis-Driven Review
By Lyu S, González-Angulo E
Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of oral malignancies, and most cases arise from oral potentially malignant disorders (OPMDs) against a background of chronic inflammation. Periodontitis, a highly prevalent chronic inflammatory disease, is increasingly implicated as a risk factor for OSCC, yet the mechanistic link between these conditions remains unclear. This review proposes that immunosenescence—the age-related decline in immune function—may provide this link. We synthesise evidence indicating that periodontitis promotes immune ageing in oral and systemic immune compartments, encompassing T-cell exhaustion, the accumulation of senescent immune cells, and a pro-inflammatory senescence-associated secretory phenotype (SASP); together, these changes progressively weaken local immunosurveillance. On this basis, we introduce the “immune-senescent switch” as a conceptual framework—explicitly distinguished from established evidence—in which senescence is hypothesised to initially act as a tumour-suppressive barrier in early OPMDs but to be converted into a tumour-promoting force by chronic, periodontitis-driven immunosenescence. We critically evaluate the supporting evidence, including the single-arm phase 2 COIS-01 trial (n = 24), in which senolytics combined with anti-PD-1 therapy achieved a 33.3% major pathological response rate in resectable head and neck squamous cell carcinoma, while emphasising the preliminary, hypothesis-generating nature of these data. Finally, we discuss emerging senotherapeutic strategies, translational gaps, and future research priorities.