The goal of this clinical trial is to learn whether neoadjuvant GV20-0251 combined with sintilimab is safe and tolerable, and to explore its preliminary antitumor activity, in adults with resectable, locally advanced head and neck squamous cell carcinoma at West China Hospital, Sichuan University. The main questions it aims to answer are: What is the incidence of dose-limiting toxicities (DLTs) during neoadjuvant treatment with GV20-0251 in combination with sintilimab in the dose-escalation phase? What is the major pathologic response (MPR) rate in resected specimens after neoadjuvant treatment? Participants will receive two 3-week cycles of neoadjuvant therapy using a 3+3 dose-escalation design (GV20-0251 at 10 mg/kg or 20 mg/kg plus fixed-dose sintilimab 200 mg, both given by intravenous infusion on Day 1 of each cycle), undergo protocol-specified safety monitoring with adverse events graded per CTCAE v5.0 and routine clinical assessments and laboratory tests, proceed to definitive surgery after neoadjuvant therapy, receive postoperative adjuvant therapy, and complete post-treatment safety follow-up and protocol-defined long-term follow-up for disease status and survival outcomes.

Inclusion Criteria:

1. Age 18 to 70 years, inclusive, at the time of signing informed consent; male or female;
2. Histologically confirmed head and neck squamous cell carcinoma (HNSCC) meeting all of the following conditions:

1). Newly diagnosed, locally advanced HNSCC without distant metastasis (excluding nasopharyngeal, salivary gland, and thyroid malignancies): Non-oropharyngeal HNSCC and HPV-negative oropharyngeal cancer: Stage III, IVA, or IVB;HPV-positive oropharyngeal cancer: Stage II or III；HPV status for oropharyngeal cancer will be determined by p16 immunohistochemistry; 2). Assessed by the head and neck surgeon as resectable and amenable to surgical treatment; 3.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 4.Adequate organ and bone marrow function, defined as follows:

1. Hematologic function:Absolute neutrophil count (ANC) ≥1.5 × 10^9/L;Platelet count (PLT) ≥80 × 10^9/L;Hemoglobin ≥8 g/dL.
2. Hepatic function:Aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN);Alanine aminotransferase (ALT) ≤2.5 × ULN;Total bilirubin (TBIL) ≤1.5 × ULN;
3. Serum albumin ≥2.8 g/dL;
4. Renal function:Serum creatinine ≤1.5 × ULN, orCreatinine clearance (CrCl) >60 mL/min;
5. Coagulation function:International normalized ratio (INR) ≤1.5;Activated partial thromboplastin time (APTT) ≤1.5 × ULN; 5.Participants must voluntarily agree to participate in the study, sign the informed consent form, and be able to comply with protocol-required visits and study procedures.

Exclusion Criteria:

1. History of other malignancies, except for malignancies considered eligible by the investigator, such as adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, or intramucosal gastrointestinal carcinoma that has been cured and has not recurred within 5 years;
2. Active autoimmune disease or history of autoimmune disease, including but not limited to immune-related neurologic disorders, multiple sclerosis, autoimmune demyelinating neuropathy, Guillain-Barré syndrome, myasthenia gravis, systemic lupus erythematosus (SLE), connective tissue disease, scleroderma, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome; participants with type 1 diabetes mellitus controlled with a stable dose of insulin may be enrolled;
3. Allergic disease, severe drug allergy history, or known hypersensitivity to macromolecular protein preparations or any component of PD-1 monoclonal antibody injection; severe hypersensitivity is defined as Grade 3 or higher according to CTCAE;
4. Prior receipt of any of the following treatments: 1) prior treatment with PD-1 antibody, PD-L1 antibody, CTLA-4 antibody, EGFR antibody, or EGFR tyrosine kinase inhibitor; 2) prior receipt of any antitumor vaccine; 3) receipt of any live vaccine for prevention of infectious disease within 4 weeks before first dose or planned use during the study, such as influenza vaccine or varicella vaccine; 4) major surgery or severe trauma within 4 weeks before first dose;
5. Requirement for systemic corticosteroid therapy (>10 mg/day prednisone or equivalent) or other immunosuppressive therapy within 14 days before study drug administration; inhaled or topical corticosteroids and physiologic replacement doses of adrenal steroids are permitted;
6. Severe medical disease, including New York Heart Association (NYHA) Class II or higher cardiac dysfunction, ischemic heart disease such as myocardial infarction or angina pectoris, clinically significant supraventricular or ventricular arrhythmias, left ventricular ejection fraction <50% by echocardiography, QTc interval >450 msec in men or >470 msec in women, or any electrocardiographic abnormality considered by the investigator to pose additional risk with the study drug;
7. Known history of interstitial lung disease, noninfectious pneumonitis, or high suspicion of interstitial lung disease, or any condition that may interfere with the detection or management of suspected drug-related pulmonary toxicity; participants with a prior history of drug-induced or radiation-induced noninfectious pneumonitis who are currently asymptomatic may be enrolled; active tuberculosis, or previous tuberculosis infection that remains uncontrolled after treatment;
8. Hyperthyroidism or organic thyroid disease; participants with hypothyroidism controlled with thyroid hormone replacement therapy may be enrolled if considered adequately controlled by the investigator and/or endocrinologist;
9. Active infection, unexplained fever during screening or within 48 hours before first dose, or use of systemic antibiotics within 1 week before signing informed consent;
10. Active hepatitis B infection (HBV DNA ≥2000 IU/mL or 10^4 copies/mL), active hepatitis C infection (positive HCV antibody with HCV RNA above the lower limit of detection of the assay), known positive history of human immunodeficiency virus (HIV) infection, or known acquired immunodeficiency syndrome (AIDS);
11. Definite history of neurologic or psychiatric disorders, such as epilepsy or dementia;
12. Known history of drug abuse or alcohol abuse within 3 months before enrollment;
13. Pregnancy or lactation; intention to conceive during treatment or within 4 months after the last dose in the participant or the participant's partner, unprotected sexual activity without contraception, or unwillingness to use adequate contraceptive measures such as condoms, intrauterine devices, or partner sterilization;
14. Receipt of any investigational drug within 4 weeks before first use of study drug, or concurrent participation in another clinical study, unless it is an observational (non-interventional) study or the follow-up phase of an interventional study;
15. Any other condition that, in the opinion of the investigator, may interfere with study participation, completion of study treatment, or follow-up.