Multidimensional immune profiling uncovers biphasic peripheral T-cell dynamics after chemoradiation in patients with locally advanced head and neck cancer.

Cisplatin-based concurrent chemoradiation (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Attempts to combine immune checkpoint inhibitors with CRT have not improved outcomes, underscoring the need to better understand CRT-driven immunologic dynamics. Here, we performed longitudinal, multidimensional profiling of peripheral immunity in patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after platinum-based CRT. CRT induced a transient reduction in tumor-reactive Th1 responses at CRT-1M, followed by marked expansion by CRT-3M. Consistently, genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic pattern with delayed upregulation at CRT-3M. Transcriptomic analyses of blood lymphocytes revealed an early shift from B-cell- to T-cell-mediated pathways over time during CRT. Integrated analyses including immunosuppressive cells and soluble mediators showed that the early decline in tumor-reactive T cells coincided with increased immunosuppressive cells, T-cell exhaustion, and elevated protumoral cytokines such as IL-8, IL-1β, and IL-10. In contrast, robust expansion of tumor-reactive T cells dominated the peripheral immune landscape at CRT-3M. Together, these data reveal the dynamic remodeling of peripheral immunity following platinum-based CRT and identify a delayed peripheral immune activation phase that may represent an optimal window for combining CRT with immune checkpoint blockade.