Moving immunotherapy ahead of chemoradiotherapy in a "sandwich" model-where tumor reduction is achieved through induction chemo-immunotherapy, immunotherapy is paused during chemoradiotherapy, and then resumed as maintenance post-radiotherapy-has shown promising potential. However, this approach still faces two main challenges: insufficient depth of tumor response and an increased risk of radiation pneumonitis.To address these issues, we investigators have designed a novel high-low mixed-dose irradiation strategy. This approach, combined with two cycles of induction chemo-immunotherapy, aims to achieve rapid tumor regression, improve disease control rates, and reduce overall lung radiation exposure.

Inclusion Criteria:

• Signed written informed consent obtained prior to the initiation of any trial-related procedures.

• Age > 18 years.

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC).

• Negative for driver gene mutations (EGFR, ALK, ROS1, RET, MET exon 14 skipping, HER2, BRAF, KRAS G12C).

• Locally advanced disease, including Stage III and selected Stage IV (where all lesions are deemed safely treatable with a radiotherapy dose > 50 Gy in 10 fractions, as assessed by a senior radiation oncologist).

• At least one thoracic lesion with a short-axis diameter > 2 cm.

• Positive hilar or mediastinal lymph nodes.

• ECOG Performance Status of 0 or 1.

• Life expectancy > 3 months.

• Adequate organ function, as defined by the following laboratory parameters:

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L.
  2. Platelet count ≥ 100 × 10⁹/L.
  3. Hemoglobin > 9 g/dL.
  4. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).
  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
  6. Serum creatinine ≤ 1.5 × ULN AND calculated creatinine clearance (using the Cockcroft-Gault formula) ≥ 60 mL/min.
  7. Adequate coagulation, defined as an International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN.
  8. Normal thyroid function, defined as Thyroid-Stimulating Hormone (TSH) within normal limits. Subjects with baseline TSH outside the normal range may be enrolled if both total T3 (or free T3) and free T4 levels are within normal limits.
  9. Cardiac enzymes within normal limits (subjects may be enrolled if the investigator judges isolated laboratory abnormalities to be clinically insignificant).

• For female subjects of childbearing potential, a negative urine or serum pregnancy test must be documented within 3 days prior to receiving the first dose of study medication (Cycle 1, Day 1). If a urine pregnancy test result is ambiguous or cannot be confirmed as negative, a serum pregnancy test is required. Non-childbearing potential is defined as being postmenopausal for at least 1 year, surgically sterile, or having undergone a hysterectomy.

• Subjects (both male and female) at risk of pregnancy must agree to use highly effective contraception (with a failure rate of <1% per year) throughout the treatment period and for 120 days after the last dose of study medication (or 180 days after the last dose of chemotherapy), whichever is later.

Exclusion Criteria:

• Patients with severe emphysema, interstitial lung changes, or COPD;
• Resting blood oxygen saturation < 93%;
• History of other malignancies requiring chemotherapy within the past 2 years;
• History of thoracic radiotherapy;
• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapies (e.g., thyroxine, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency) are not considered systemic treatment;
• Current use of systemic corticosteroids (>10 mg daily prednisone or equivalent) or any form of immunosuppressive therapy within 7 days prior to the first study dose (excluding topical, nasal, inhaled, or local corticosteroids); *Note: Physiological corticosteroid doses (≤10 mg/day prednisone or equivalent) are permitted.*
• Known history of allogeneic organ transplantation (except corneal transplant) or allogeneic hematopoietic stem cell transplantation;
• Known allergy to any component of the study drug or its excipients;
• Known history of HIV infection (positive HIV1/2 antibodies);
• Untreated active hepatitis B (defined as HBsAg positive with detectable HBV-DNA above the upper limit of normal at the local laboratory);

Note: Hepatitis B subjects meeting the following criteria may be enrolled:

a) HBV DNA < 1000 copies/mL (200 IU/mL) before the first dose, with ongoing antiviral therapy throughout chemotherapy to prevent reactivation; b) Subjects who are anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV DNA (-) do not require prophylactic antiviral therapy but require close monitoring for reactivation.

• Active HCV infection (positive HCV antibody with detectable HCV-RNA above the lower limit of detection);

• Administration of live vaccines within 30 days prior to the first dose (Cycle 1, Day 1); Note: Inactivated seasonal influenza vaccines are permitted within 30 days prior to the first dose; live attenuated intranasal influenza vaccines are not allowed.

• Pregnant or breastfeeding women;

• Any severe or uncontrolled systemic disease, including but not limited to:

  1. Resting ECG showing clinically significant uncontrolled abnormalities in rhythm, conduction, or morphology (e.g., complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation);
  2. Unstable angina, congestive heart failure, or chronic heart failure classified as NYHA Class ≥2;
  3. Arterial thrombosis, embolism, or ischemia within 6 months prior to enrollment (e.g., myocardial infarction, unstable angina, stroke, or transient ischemic attack);
  4. Poorly controlled hypertension (systolic BP >140 mmHg or diastolic BP >90 mmHg);
  5. History of non-infectious pneumonitis requiring corticosteroids within 1 year prior to the first dose, or current clinically active interstitial lung disease;
  6. Active tuberculosis;
  7. Active or uncontrolled infection requiring systemic therapy;
  8. Clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction;
  9. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
  10. Poorly controlled diabetes (fasting blood glucose >10 mmol/L);
  11. Urine dipstick showing protein ≥++ with confirmed 24-hour urine protein >1.0 g;
  12. Psychiatric disorders that may interfere with treatment compliance;

• Any other condition (e.g., medical history, disease, ongoing treatment, or laboratory abnormality) that may interfere with study results, compromise patient participation, or pose additional risks-in the investigator's judgment-making the subject unsuitable for study enrollment.