Background: Seeking out a more effective and less-toxic regimen is necessary for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). The aim of this study is to evaluate the efficacy and safety of neoadjuvant anti-programmed cell death-1 antibody tislelizumab combined with APF (albumin-bound paclitaxel, platinum and fluorouracil) followed by surgery or concurrent chemoradiotherapy. Methods: In this prospective, single-center, single-arm clinical study, previously untreated patients with locally advanced HNSCC, aged 18-75 years without severe comorbidities and contraindications to immunotherapy are enrolled. Eligible patients received A (200 mg/m² d1) P (60 mg/m² d1- d2) F (600 mg/m² CIV120h) induction chemotherapy along with tislelizumab (200 mg d1) every 3 weeks. The curative effect is evaluated (RECIST 1.1) after 3 cycles and a multidisciplinary team discuss whether to perform surgery. For patients undergoing surgery, treatment is completed if there is no residual and extra-capsular lymph node invasion; in case of positive surgical margin, or extracapsular lymph node invasion, or residual lymph nodes, patient will receive concurrent chemoradiotherapy (tumor bed and neck lymph drainage area 66 Gy~70 Gy, P 60 mg/m²). Those not suitable for surgery will receive radical concurrent chemoradiotherapy (GTV 66Gy~70Gy, PTV 50Gy, P 60 mg/m²) within 3 weeks after neoadjuvant treatment. The primary endpoint of efficacy evaluation is the pathological complete response (pCR) rate. Safety evaluation indicators include vital signs, laboratory indicators and adverse events (NCI CTC AE4.0). Results: From Apr 2022 to Jan 2023, 12 patients are screened and enrolled. For the 7 patients who complete 3 cycles of neoadjuvant therapy, 3 patients (42.8%) successfully undergo surgery, with 2 patients (28.5%) achieving pCR and 1 patient (14.3%) achieving major pathological response (MPR). For the other 4 patients, 1 patient (14.3%) achieve pCR by multipoint biopsy of the primary lesion and 2 patients (28.5%) obtain radiologic partial response (PR) by MRI. 1 patient’ lymph nodes tend to increase during radiotherapy and that patient withdraw from clinical trial and undergo salvage surgery. The objective response rate (ORR) of neoadjuvant treatment is 85.7% and pCR rate is 42.9%. Grade 2 or higher AEs during neoadjuvant therapy include grade 2 liver function damage (n = 1, 8.3%), grade 3 myelosuppression (n = 1, 8.3%). 1 (8.3%) patient developed radiation-related oral mucositis (RTOG 2). No other obvious adverse reactions of radiotherapy, chemotherapy or immunotherapy are observed. Conclusions: Combining Tislelizumab with APF followed by surgery or radical concurrent chemoradiotherapy is feasible and effective in patients with locally advanced HNSCC, and further studies are needed to verify its effectiveness and safety.