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), but clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), associated with oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. While chronic interferon signaling impairs CD8 T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analyzing human OSCC datasets, we observed 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 ISG15 exposure induces severe dysfunction via an endocytic mechanism independent of LFA-1 signaling. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8 T cells though these cells were dysfunctional. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell functionality in ISG15-expressing tumors. Our findings indicate that chronic ISG15 exposure promotes CD8 T cell dysfunction; however, these cells remain responsive to PD-1 blockade. This study reveals ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.