Inclusion Criteria:
1. Age: 18 to 70 years old.
2. Diagnosis: Histopathologically confirmed head and neck squamous cell carcinoma (HNSCC) of the oropharynx, oral cavity, hypopharynx, or larynx, classified as Stage III or IV A according to the AJCC Cancer Staging Manual (8th Edition).
3. Measurable Disease: At least one measurable primary lesion per RECIST 1.1 criteria.
4. Treatment Status: Treatment-naïve patients with no prior therapy for the disease.
5. Performance Status: ECOG performance status of 0-1.
6. Surgical Eligibility: Deemed eligible for elective standard surgery followed by standard adjuvant chemoradiotherapy/radiotherapy, as assessed by the investigator.
7. Autoimmune Disease: No active autoimmune diseases.
8. Concurrent Malignancy: No concurrent malignancies.
9. Life Expectancy: ≥6 months.
10. Biomarker Testing: Available tumor tissue samples for PD-L1 testing via Combined Positive Score (CPS) using 22C3 pharmDx assay (DAKO).
11. Hematologic Parameters:
* ANC ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥100 g/L, WBC ≥3.5×10⁹/L.
* No transfusion within 7 days or bleeding tendency.
12. Liver Function: ALT, AST, ALP, and total bilirubin ≤1.5× upper limit of normal (ULN).
13. Renal Function: Serum creatinine ≤1.5× ULN or creatinine clearance \>60 mL/min.
14. HPV Status: HPV status confirmed via p16 immunohistochemistry (IHC) and/or in situ hybridization (ISH).
15. Informed Consent: Voluntarily participates and signs informed consent. For participants unable to consent due to incapacity, consent must be provided by a legally authorized representative. For illiterate participants, an impartial witness must attest to the informed consent process.
Exclusion Criteria:
1. Cachexia or multiple organ failure.
2. Active autoimmune disease(s) requiring systemic treatment (excluding vitiligo, resolved childhood asthma/atopy, or controlled hypothyroidism on hormone replacement).
3. Concurrent second primary malignancy (e.g., esophageal cancer).
4. Severe active infection requiring systemic therapy.
5. Uncontrolled comorbid medical conditions that may compromise protocol compliance, per investigator judgment, including:
* Severe cardiovascular/cerebrovascular diseases,
* Uncontrolled diabetes/hypertension,
* Active peptic ulcer,
* Uncontrolled infections.
6. Dementia, altered mental status, or cognitive impairment affecting informed consent or questionnaire completion.
7. Grade ≥2 peripheral neuropathy (per CTCAE v5.0).
8. Grade ≥2 hearing impairment (per CTCAE v5.0).
9. History of malignancy within the past 5 years (excluding cured non-melanoma skin cancer or carcinoma in situ).
10. Known HIV-positive status or AIDS.
11. Nasopharyngeal carcinoma or squamous cell carcinoma originating outside oral cavity, oropharynx, hypopharynx, or larynx (e.g., sinonasal tract, paranasal sinuses, or unknown primary).
12. Participation in another interventional clinical trial or use of investigational drugs within 30 days prior to screening.
13. Systemic glucocorticoids (\>10 mg/day prednisone equivalent) or immunosuppressive agents within 14 days prior to randomization.
• Exceptions: Inhaled/topical steroids or physiologic replacement doses for adrenal insufficiency.
14. Pregnancy, breastfeeding, or refusal of contraception by subjects of childbearing potential.
15. Active infection requiring treatment or systemic antimicrobial use within 1 week prior to first dose.
16. Live vaccines administered within 30 days before first dose or during the study.
17. Vulnerable populations (e.g., severe psychiatric disorders, cognitive impairment, critically ill patients, prisoners, pregnant individuals).
18. Other conditions deemed by the investigator to preclude safe study participation.
