Background: Neoadjuvant immunotherapy and chemotherapy has been explored in phase I/II clinical studies in head and neck squamous cell carcinoma (HNSCC), confirming its safety and efficacy. However, the pathological complete response (pCR) / major pathological response (MPR) rate still needed for improvement. Recent studies revealed that low dose radiotherapy can overcome immunosuppressive tumors by reversing immune desertification when combining immunotherapy. Here, we conducted this clinical trial to explore the efficacy and safety of neoadjuvant low-dose radiotherapy, PD-1 inhibitor, combined with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma. Methods: This was an open-label, single-arm, phase II clinical trial. Patients with untreated, histologically confirmed HNSCC staging III-IVB were included. The eligible patients were scheduled to be administrated neoadjuvant low-dose radiotherapy (1GY/1F, D1, D2, D8, D15, Q3W), PD-1 inhibitor tislelizumab (200 mg D1, Q3W), combined with albumin-bound paclitaxel (100mg/m2, D1, D8, D15, Q3W) and cisplatin (25mg/m2, D1, D8, D15, Q3W) for two cycles. Radically surgical resection was planned to conduct 3-4 weeks after neoadjuvant therapy. The primary endpoint was pCR rate. The second endpoints consisted of MPR rate, objective response rate (ORR), R0 resection rate, safety, non-surgery-delay rate and quality of life. 25 patients will finally be enrolled in this study. Simon's two-stage design was adopted, and 10 patients should be included in the first stage. If 2 or more of the first 10 patients reached pCR, the second stage would be successfully entered. Results: By Jan 10, 2023, 10 patients were enrolled. 7 out of 10 patients successfully received the study regimen and finished the operation on schedule. Our primary endpoint of first stage was met. 4/7 (57%) patients achieved pCR at the primary site , 3/7 (43%) patients achieved MPR. The pCR/MPR rate was 100%. R0 resection rate was 100%. Totally 9 patients underwent MRI scan pre and post neoadjuvant therapy, and the assessment per RESCIST criteria were as follow: 0/9 (0%) CR, 6/9 (66%) PR, 3/9 (33%) SD. The treatment-related adverse events (TRAEs) were manageable. The most shared adverse events of grade 1/2 were anorexia (89%), anemia (89%) and nausea (66%). No surgical delay was observed. Conclusions: Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin contributed to an outstanding pCR/MPR rate of 100% (pCR rate of 57% and MPR rate of 43%) at present, and was generally tolerated in locally advanced HNSCC. The second stage is ongoing. Clinical trial information: NCT05343325. Research Sponsor: BeiGene Co., Ltd. and CSPC Co., Ltd.