Iparomlimab and Tuvonralimab Plus Chemotherapy Before Surgery for Stage III Lung Cancer

Inclusion Criteria:

1. Voluntarily join the study and sign the Informed Consent Form (ICF).
2. ≥18 years old, male or female.
3. Histologically or cytologically confirmed T\<sub\>any\</sub\>N2b stage NSCLC (American Joint Committee on Cancer \[AJCC\] 9th edition). Lymph node status must be confirmed by endobronchial ultrasound (EBUS/EUS) or mediastinoscopy for mediastinal lymph nodes. For left-sided stations 5/6 lymph nodes, parasternal mediastinoscopy is recommended to confirm lymph node status; if mediastinoscopy is not performed, station 5/6 lymph node status is diagnosed based on imaging diagnostic criteria.
4. Based on MDT assessment (which must include a thoracic surgeon specialized in oncology), the primary NSCLC is deemed to be completely resectable (R0).
5. At least one measurable lesion as assessed by the investigator per RECIST v1.1.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
7. Adequate organ function meeting the following requirements (no use of any blood components, cell growth factors, etc., within 14 days before the first dose):

   1. Absolute neutrophil count ≥1.5×10⁹/L;
   2. Platelet count ≥100×10⁹/L;
   3. Hemoglobin ≥90 g/L;
   4. Serum creatinine ≤1.5×upper limit of normal (ULN) or creatinine clearance (CLcr) ≥40 mL/min calculated by the Cockcroft-Gault formula;
   5. Total bilirubin ≤1.5×ULN (patients with Gilbert's syndrome may have ≤3×ULN);
   6. AST and ALT ≤3×ULN;
   7. International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≤1.5×ULN, unless the subject is receiving anticoagulant therapy;
   8. Left ventricular ejection fraction (LVEF) ≥50%.
8. For female patients of non-surgical sterilized or childbearing potential, must agree to use a medically accepted contraceptive method (e.g., intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 3 months after the study treatment period ends; female patients of childbearing potential who are not surgically sterilized must have a negative serum or urine HCG test within 72 hours before the first dose; and must be non-lactating; for male patients with partners of childbearing potential, must agree to use effective contraception during the trial and for 3 months after the last dose of Iparomlimab/Tuvonralimab.

Exclusion Criteria:

1. Known presence of EGFR or ALK positive mutations.
2. History of or concurrent other malignancy within the past 5 years (excluding adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical surgery, ductal carcinoma in situ after radical surgery).
3. Prior receipt of any anti-tumor therapy for the current lung cancer (e.g., radiotherapy, chemotherapy, targeted therapy, ablation, or other systemic or local anti-tumor therapies).
4. Current use of immunosuppressants or systemic hormone therapy for immunosuppressive purposes (dose \>10 mg/day prednisone or equivalent) and continued use within 2 weeks before enrollment (Note: Inhaled or topical corticosteroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease).
5. Any active autoimmune disease or history of autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial pneumonia, pulmonary fibrosis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism.

   1. Subjects with hypothyroidism controlled by hormone replacement therapy alone are eligible;
   2. Subjects with skin diseases not requiring systemic treatment such as vitiligo, psoriasis, alopecia, type 1 diabetes, or childhood asthma that has completely resolved and requires no intervention in adulthood are eligible;
   3. Patients with asthma requiring medical intervention with steroids are not eligible.
6. History of allogeneic hematopoietic stem cell transplantation or organ transplantation (except corneal transplantation).
7. Congenital or acquired immunodeficiency (e.g., HIV-infected individuals).
8. Uncontrolled active hepatitis B (defined as positive hepatitis B surface antigen \[HBsAg\] test at screening with concurrent HBV-DNA test value above the upper limit of normal of the research center's laboratory; subjects with HBV-DNA \<500 IU/mL measured within 28 days before study drug administration and who have received standard local antiviral therapy for at least 4 weeks and are willing to continue antiviral therapy during the study may be enrolled). Subjects with active hepatitis C (defined as positive hepatitis C virus antibody \[HCsAb\] test at screening and positive HCV-RNA).
9. History of severe allergic reactions to other monoclonal antibodies.
10. Vaccination with live vaccine within 30 days before the first dose of study treatment (continuing until 90 days after the last dose of study treatment). Note: Live vaccines include but are not limited to measles, mumps, rubella, varicella/zoster (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Inactivated seasonal influenza vaccines, inactivated COVID-19 vaccines, etc., are permitted.
11. Clinically significant cardiovascular or cerebrovascular diseases, including but not limited to:

    1. Myocardial infarction or unstable angina pectoris within 6 months before the first dose;
    2. Stroke or transient ischemic attack within 6 months before the first dose;
    3. Hypertension not controlled with optimal antihypertensive therapy (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);
    4. Clinically significant arrhythmia that has been stable for ≥14 days before the first dose may be enrolled;
    5. Congestive heart failure (New York Heart Association \[NYHA\] functional class III-IV);
    6. Myocarditis.
12. Systemic infection or other severe infection requiring intravenous antibiotics for \>7 days within 2 weeks before the first study treatment, or unexplained fever \>38.5°C during screening or before enrollment (fever due to tumor causes as judged by the investigator is excluded).
13. Any other condition that, in the investigator's judgment, might affect the study results or lead to premature termination of the study, such as alcoholism, drug abuse, other severe diseases (including mental illness) requiring concomitant treatment, severe laboratory abnormalities, or family or social factors, which could affect patient safety.