Radiation-induced remodeling of the T cell landscape in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy associated with high recurrence rates and substantial treatment-related morbidity. Radiation therapy remains a central component of the management of locoregional disease. Although radiation directly damages malignant cells through DNA breaks and associated stress pathways, radioresistance remains common, and a proportion of patients continue to develop locoregional recurrence or distant metastasis despite adequate locoregional control. Recent advances in single-cell and spatiotemporal profiling of HNSCC have clarified how radiation alters systemic and intra-tumoral T cell populations and produces a post-radiation tumor microenvironment that provides insufficient support for the robust priming of new tumor-reactive responses. These insights help explain why clinical trials combining radiotherapy with immune checkpoint inhibitors have not reproduced the synergy predicted by preclinical models. At the same time, they point to opportunities to design radiation as a programmable immune adjuvant. In this review, we summarize emerging mechanistic data on radiation-induced remodeling of the T cell landscape, outline the barriers that limit productive immune priming after treatment, and discuss strategies aimed at restoring effective anti-tumor immunity in the post-radiation setting.