Lattice radiation therapy (LRT) is a spatially fractionated thoracic radiotherapy technique that creates alternating high- and low-dose regions within primary lung tumors and metastatic lymph nodes to strengthen local tumor suppression and reduce radiation injury to normal thoracic organs. This study aims to evaluate the efficacy and safety of combining LRT with consolidation chemoimmunotherapy in unresectable stage III LA-NSCLC patients who show suboptimal tumor response to prior neoadjuvant chemoimmunotherapy, through a single-arm Phase II clinical trial. Patients will receive thoracic LRT delivered by a medical linear accelerator. High-dose spherical sub-targets will be contoured within the gross tumor volume of primary lung lesions and regional nodal metastases under standardized dose constraints to spare the lung, heart and esophagus. All enrolled subjects will receive sequential consolidation chemoimmunotherapy administered within one week after finishing LRT. Tumor response, treatment-related adverse events, local tumor control and long-term survival outcomes will be prospectively tracked throughout treatment and long-term follow-up.

This open-label, single-arm Phase II clinical trial investigates the combination of lattice radiation therapy (LRT) and subsequent consolidation chemoimmunotherapy for patients with unresectable stage III locally advanced non-small cell lung cancer who only achieved limited tumor regression after standard neoadjuvant chemoimmunotherapy induction. LRT, a spatially fractionated radiotherapy technique, generates interleaved high- and low-dose zones inside tumor tissue to enhance local anti-tumor activity while minimizing radiation toxicity to surrounding healthy chest organs. Eligible participants will complete standardized thoracic LRT targeting primary lesions and involved lymph nodes following institutional contouring rules and dose restrictions. Consolidation chemoimmunotherapy will be initiated shortly after the end of radiotherapy. The study will continuously monitor all treatment-related and immune-related adverse events, evaluate therapeutic efficacy via regular imaging scans, and collect long-term survival data. Trial results will provide clinical evidence about the clinical value and safety profile of LRT plus consolidation chemoimmunotherapy for this high-risk LA-NSCLC subgroup with insufficient response to prior neoadjuvant systemic therapy.

Inclusion Criteria:

1. Histologically confirmed unresectable stage III locally advanced non-small cell lung cancer (LA-NSCLC).
2. Received at least 2 cycles of standard neoadjuvant chemoimmunotherapy, with suboptimal tumor response verified by post-induction radiological evaluation.
3. Age ≥ 18 years old.
4. ECOG performance status of 0 or 1.
5. Adequate hematologic, hepatic and renal function to complete radiotherapy and consolidation systemic therapy.
6. Voluntarily sign written informed consent and be capable of following study-related procedures.

Exclusion Criteria:

1. Prior thoracic radiotherapy history.
2. Active uncontrolled autoimmune disorders or persistent severe immune-related adverse events.
3. Untreated symptomatic brain metastases.
4. Severe irreversible cardiac, pulmonary, liver or renal dysfunction that cannot tolerate combined radiotherapy and immunotherapy.
5. Pregnant or breastfeeding women.
6. Concurrent or previous other malignant tumors within 5 years, except cured basal cell skin cancer and cervical carcinoma in situ.
7. Any absolute contraindication to lattice radiation therapy or immune checkpoint inhibitor.