The goal of this clinical trial is to evaluate the efficacy and safety of a novel combination therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). The therapy combines the JAK1 inhibitor Sulfamethoxazole, the anti-PD-L1 antibody Adebrelimab, and chemotherapy (Nab-paclitaxel + Cisplatin) as a neoadjuvant treatment (given before surgery). The main questions it aims to answer are:

• For patients with resectable locally advanced HNSCC: Can this combination improve the pathological complete response (pCR) rate (the absence of viable cancer cells in the surgical specimen) compared to current neoadjuvant therapies?
• For patients with potentially resectable or unresectable locally advanced HNSCC: Can this combination improve the objective response rate (ORR) (the percentage of patients with significant tumor shrinkage), potentially making surgery possible or reducing its scope?

Researchers will also assess secondary outcomes including event-free survival (EFS), overall survival (OS), and the safety profile of the combination.

Participants will:

• Receive neoadjuvant treatment with the combination of Sulfamethoxazole, Adebrelimab, and chemotherapy. A key feature is the timed sequencing of the JAK inhibitor, which will be started on day 8 of each treatment cycle.
• Be evaluated for surgery after the neoadjuvant treatment. For those who undergo surgery, the pathological response will be analyzed.
• Have regular follow-up assessments, including imaging studies (such as CT or MRI scans) and safety monitoring, to evaluate long-term treatment response, survival, and side effects.
• Provide tissue and/or blood samples for exploratory biomarker analysis (e.g., Interferon-Stimulated Gene signature) to help identify patients who benefit most from this treatment.

Head and Neck Squamous Cell Carcinoma (HNSCC) represents a significant and growing health burden in China, with approximately 60% of new patients diagnosed at locally advanced (Stage III/IV) disease. Despite the application of multidisciplinary team (MDT) approaches, the prognosis for these patients remains poor, characterized by a 2-year recurrence rate of 50%-60%, a 20%-30% rate of distant metastasis, and a 5-year overall survival (OS) rate below 50%. Standard-of-care for locally advanced HNSCC involves surgery ± radiotherapy/chemoradiotherapy for resectable cases and platinum-based concurrent chemoradiotherapy (CRT) for unresectable cases. However, significant unmet therapeutic needs persist.

The advent of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, has revolutionized treatment for recurrent/metastatic HNSCC, prompting exploration in the neoadjuvant setting. Previous studies suggest that neoadjuvant immunotherapy combined with chemotherapy can improve pathological complete response (pCR) rates in resectable locally advanced HNSCC, potentially increasing operability or reducing the extent of surgery to better preserve organ function. Adebrelimab is a novel, domestically developed humanized anti-PD-L1 monoclonal antibody. It blocks the PD-1/PD-L1 pathway to reactivate anti-tumor immunity and is designed for high specificity towards PD-L1, potentially leading to a favorable safety profile. Its efficacy and safety, combined with chemotherapy, have been demonstrated in cancers like extensive-stage small cell lung cancer and esophagogastric junction adenocarcinoma.

Recent groundbreaking research published in Science (June 2024) highlights a promising strategy to overcome ICI resistance by combining ICIs with JAK inhibitors. This combination can increase anti-tumor T and NK cell numbers and reverse T-cell exhaustion. Crucially, JAK inhibitors can prevent T-cell exhaustion induced by Type I Interferon (IFN-I) signaling. When combined with ICIs, they restore T-cell function, leading to enhanced anti-tumor efficacy. A key finding is that a temporally sequenced administration strategy-delaying the initiation of the JAK inhibitor-can preserve beneficial early immune activation while counteracting resistance mechanisms, as validated in preclinical models. Furthermore, an Interferon-Stimulated Gene (ISG) signature (e.g., IFIT1/MX1) may serve as a predictive biomarker to identify patients with active interferon signaling who are more likely to benefit from this approach.

Based on this compelling rationale, this clinical trial aims to investigate the combination of a JAK1 inhibitor with neoadjuvant chemoimmunotherapy in locally advanced HNSCC. A critical feature of the trial design is the implementation of the temporally sequenced dosing strategy for the JAK inhibitor, initiating it from day 8 of each treatment cycle to optimize the immune response and mitigate resistance.

In summary, this study seeks to address the critical unmet needs in locally advanced HNSCC by evaluating a novel, mechanistically rational combination of a JAK1 inhibitor (sulfamethoxazole) with neoadjuvant chemoimmunotherapy (adebrelimab + nab-paclitaxel/cisplatin), utilizing an innovative timed-sequencing approach. The trial aims to demonstrate improved efficacy and manageable safety, while pioneering biomarker-driven strategies for patient selection in this challenging disease.

Inclusion Criteria:

1. ECOG Performance Status of 0-1.

2. Histologically and/or cytologically confirmed Stage III-IVA head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, or larynx).

3. Classified according to the Asia-Pacific multidisciplinary consensus (Y.Guo et al., Oral Oncol 2024):

   • Cohort A: Resectable** (amenable to upfront surgery): T2N2-3M0, T3-4N0-2M0 (AJCC 8th edition).
   • Cohort B: Potentially Resectable:** Cases with relative contraindications to surgery (e.g., cervical lesion directly invading skin, anterior 2/3 tongue tumor extending below the hyoid level, extension to the vallecula) or where surgery would cause significant disfigurement/functional loss, requiring discussion by an MDT (head & neck surgery, radiology) to weigh risks vs. non-surgical options.
   • Cohort C: Unresectable: Tumor extensively invading skull base, extending to nasopharynx/deep nasopharyngeal wall, invading/encasing carotid artery, extending to mediastinal structures, prevertebral fascia, or cervical spine; T3-4 (N0-3) or any N2a-3 (T1-4) M0 (AJCC 8th edition).

4. Biomarker: Peripheral blood flow cytometry analysis showing that PD-1+TIM-3+CD8+ exhausted T cells account for >10% of CD8+ T cells.

5. Adequate baseline organ function within 14 days prior to enrollment:

   • Hematological: White Blood Cell count (WBC) ≥4000/μL, Absolute Neutrophil Count (ANC) ≥2000/μL, Hemoglobin (HGB) ≥9 g/dL, Platelet count (PLT) ≥100,000/μL.
   • Renal: Serum creatinine <1.5 times the Upper Limit of Normal (ULN) OR Creatinine Clearance (CrCl) >60 mL/min (calculated by Cockcroft-Gault formula).
   • Hepatic: Total bilirubin ≤1.5x ULN (except subjects with Gilbert's syndrome, who may have total bilirubin <3x ULN); Aspartate Aminotransferase (AST) / Alanine Aminotransferase (ALT) ≤3x ULN; Alkaline Phosphatase (ALP) ≤3x ULN; Albumin (ALB) ≥3 g/dL.

6. Ability to understand and willingness to sign the Informed Consent Form. Subjects must be willing and able to comply with the protocol, including receiving treatments and scheduled visits/examinations, including follow-up.

Exclusion Criteria:

1. Prior treatment with immunotherapy (anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 agents) or JAK inhibitors. History of severe allergic reactions to any component of monoclonal antibodies.
2. Active autoimmune disease or condition requiring immunosuppressive therapy. Subjects requiring systemic corticosteroids or other immunosuppressive drugs prior to enrollment.
3. History of other active malignancies or active infections (including tuberculosis and hepatitis); uncontrolled infections (HIV, HBV, HCV).
4. Severe cardiac or pulmonary dysfunction, including severe cardiac insufficiency (e.g., NYHA Class III or higher) or severe pulmonary dysfunction (e.g., FEV1 <50% predicted); history of thrombotic diseases, coagulation disorders (Prothrombin Time (PT) >16 seconds, Activated Partial Thromboplastin Time (APTT) >53 seconds, Thrombin Time (TT) >21 seconds, Fibrinogen (FIB) <1.5 g/L), bleeding tendency, or current thrombolytic/anticoagulant therapy.
5. Pregnant or lactating women. Subjects unwilling to use effective contraception during the study period.