This prospective, single-arm, Phase II study aims to evaluate the efficacy, safety, and surgical conversion rate of Cetuximab combined with Tislelizumab and chemotherapy for unresectable LA HNSCC.

This study plans to enroll 42 patients. After screening and qualifying the patients, they will be given the treatment of Cetuximab combined with Tislelizumab and the TP chemotherapy regimen. One cycle lasts for 3 weeks, and a total of 3 cycles will be carried out, followed by efficacy evaluation.

1. Patients evaluated as resectable will undergo surgical treatment. After the surgery, based on the postoperative pathology, it will be determined whether radiotherapy is needed. And then, 1 cycle of combined chemotherapy will be continued, followed by 1 - year maintenance treatment with Tislelizumab.
2. Patients evaluated as unsuitable for surgery will receive radical radiotherapy, followed by 1 - year maintenance treatment with Tislelizumab, until disease progression, intolerable adverse reactions occur, or the patient refuses to continue treatment.

Inclusion Criteria:

1. The subject voluntarily participates, signs the Informed Consent Form (ICF), and is able to comply with the study procedures;

2. Patients with locally advanced head and neck squamous cell carcinoma confirmed by cytology or histology, for whom complete surgical resection is difficult;

3. No prior treatment for head and neck squamous cell carcinoma;

4. No prior treatment with cetuximab or PD-(L)1 inhibitors;

5. At least one measurable lesion according to RECIST v1.1;

6. No gender restriction, age ≥18;

7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

8. Expected survival period ≥ 3 months;

9. Organ function levels meet the following criteria:

   1. Blood routine: Hemoglobin ≥90 g/L, absolute neutrophil count (ANC) ≥1.5×10^9/L, platelets ≥90×10^9/L;
   2. Blood biochemistry: ALT, AST ≤2.5×ULN (≤5×ULN if liver metastasis is present), total serum bilirubin ≤1.5×ULN, serum creatinine ≤1.5×ULN, serum albumin ≥30 g/L;
   3. Cardiac function: Left ventricular ejection fraction >50% as shown by echocardiography.

10. Women of childbearing potential must have taken reliable contraceptive measures or undergone a pregnancy test (serum or urine) within 7 days before enrollment, with a negative result, and be willing to use appropriate contraceptive methods during the trial and for 8 weeks after the last administration of the trial drug.

Exclusion Criteria:

1. Previous anti-tumor treatments received (including chemotherapy, radiotherapy, surgery, immunotherapy, etc.);
2. Known or suspected allergy to any component of cetuximab or PD-(L)1 monoclonal antibodies, as well as to the chemotherapeutic drugs paclitaxel and cisplatin;
3. Patients with hypertension that cannot be controlled to normal range with antihypertensive medications (systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg), patients with coronary heart disease of grade II or above, grade II arrhythmia (including QTc interval prolongation >470 ms), and grade I cardiac insufficiency;
4. History of autoimmune diseases or autoimmune disease history (such as colitis, hepatitis, hyperthyroidism, including but not limited to these diseases or syndromes), immunodeficiency history, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation and allogeneic bone marrow transplantation;
5. Uncontrolled active hepatitis B (HBV DNA ≥ 1000 IU/mL) or active hepatitis C (positive hepatitis C antibody) patients;
6. Patients with active tuberculosis (with exposure history or positive tuberculosis test; accompanied by clinical and/or imaging manifestations);
7. Patients who have undergone major surgery within 4 weeks before the first dose or whose wounds have not fully healed;
8. Patients with a clear tendency to bleed;
9. Patients with severe complications such as pyloric obstruction, upper gastrointestinal bleeding, gastrointestinal perforation, obstructive jaundice, severe malnutrition, etc.;
10. Patients who have experienced abdominal fistula, gastrointestinal perforation, or abdominal abscess within 6 months before enrollment;
11. Imaging shows that the tumor has invaded important blood vessels or the investigator judges that the patient's tumor is highly likely to invade important blood vessels during treatment, leading to fatal massive bleeding;
12. History of interstitial lung disease, non-infectious pneumonia, or uncontrolled diseases, including pulmonary fibrosis, acute lung disease, etc.;
13. Patients with active brain metastasis;
14. Patients with other malignant tumors within 5 years (except for completely cured cervical carcinoma in situ or basal cell or squamous cell skin cancer);
15. Pregnant or breastfeeding women;
16. Patients with severe concomitant diseases that endanger patient safety or affect the completion of the study, as judged by the investigator, and those whom the investigator considers unsuitable for inclusion.