Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma

Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analysis of human OSCC datasets revealed significant enrichment of the ISG core score—including ISG15—in tumors compared to adjacent non-tumor tissues. Using a novel in vitro model of human T cell dysfunction, we found that acute ISG15 exposure enhances CD8+ T cell effector functions, whereas prolonged exposure induces severe dysfunction via a CD11a/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T cell dysfunction, but these cells remain responsive to PD-1 blockade. This study identifies ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.