<h3>Purpose/Objective(s)</h3> Treatment options for advanced, recurrent, or metastatic (A/R/M) head and neck squamous cell carcinoma (HNSCC) comprise systemic therapies, including immune checkpoint inhibitors (ICI) with pembrolizumab, and palliative radiotherapy (RT). Pembrolizumab immunotherapy alone is associated with a modest response rate and favorable toxicity profile. This pilot study aims to assess the tolerability, clinical and immune response of adding 1-3 short courses of Quad-Shot radiotherapy to immunotherapy with pembrolizumab (QuadShot-IO). <h3>Materials/Methods</h3> In this prospective, single-arm pilot study, 15 patients with A/R/M HNSCC will be treated with pembrolizumab every 3 weeks at a dose of 200 mg/m<sup>2</sup>. Quad-Shot RT (14.8 Gy in 4 twice-daily fractions over 2 days) will be delivered to gross disease within the head/neck prior to cycles 3, 7, and 12. Metastatic site(s), if present, will not be irradiated. Prior RT is allowed. At least one Quad-Shot must be delivered, the remaining treatments (up to a total dose of 44.4 Gy in 12 fractions) are at the discretion of the treating radiation oncologist. Radiographic response assessments will be performed every 5 cycles and pembrolizumab will be continued until progression or intolerance or up to 35 cycles. Blood and saliva will be collected before and after the first and second cycles of pembrolizumab and before and after each Quad-Shot RT. <h3>Results</h3> The primary objective is to evaluate the overall response measured by RECIST version 1.1. Secondary objectives include response rate at the RT target lesion(s) and non-target sites, the durability of response, progression-free survival, overall survival, and patient-reported toxicity measured by the PRO-CTCAE version 1.0. Correlative analyses propose to engage high-throughput technologies to evaluate the hypothesized immunosensitizing effect of repetitive courses of low-dose RT, and to participate in the current research effort to uncover biomarkers of response to PD-1 inhibitors and describe an immune-sensitive profile. Based on our previous results, this study will utilize immune-regulatory microRNA response measured in blood and saliva to guide the timing of further, more comprehensive evaluations of the immune response, with proteomics & metabolomics and single cell RNA sequencing. <h3>Conclusion</h3> This prospective study will investigate the response outcomes of the combination of low-dose Quad-Shot RT and pembrolizumab for patients with A/R/M HNSCC. Correlative analyses using a multi-omics approach will provide crucial preliminary data on the immunomodulatory impact of low-dose Quad-Shot RT on response to PD-1 inhibitors as well as the effect on tumor response.