Immune-preserving radiotherapy and perioperative immunotherapy in stage III NSCLC: a narrative review of current management and future directions for IIIA/IIIB NSCLC

Background and Objective: Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with outcomes limited by distant failure, treatment-related toxicities, and loss of immune fitness during chemoradiation. Randomized trials support perioperative immunotherapy (IO) for resectable disease and consolidation durvalumab after concurrent chemoradiotherapy (cCRT) for unresectable disease. Immune-preserving radiotherapy (RT)—encompassing immune organ-at-risk (iOAR) and effective dose to immune cells (EDIC)-aware planning, judicious hypofractionation, and stereotactic body radiation therapy (SBRT) or spatially fractionated radiation therapy (SFRT)—is an emerging lever to optimize immune competence during treatment. This study aims to synthesize contemporary evidence for stage IIIA/IIIB management through a dual-track framework (resectable versus unresectable disease), outline practical algorithms integrating surgery, RT, and systemic therapy, and highlight translational strategies including SFRT and tumor-infiltrating lymphocyte (TIL)-based approaches, while clearly distinguishing established standards from investigational concepts.

Methods: We conducted a narrative review of pivotal trials and practice-shaping studies, emphasizing perioperative IO (neoadjuvant chemo-IO ± adjuvant IO), the PACIFIC paradigm, RT dose/fractionation strategies, and approaches to mitigate RT-related lymphopenia. We propose an evidence-anchored clinical pathway and a checklist for immune-preserving RT.

Key Content and Findings: Neoadjuvant nivolumab-chemotherapy improves pathological complete response (pCR), event-free survival (EFS), and overall survival (OS) in resectable disease (CheckMate 816). Perioperative pembrolizumab (KEYNOTE-671), durvalumab (AEGEAN), and nivolumab (CheckMate 77T) significantly prolong EFS. In unresectable stage III, durvalumab after cCRT confers durable OS benefit (5-year OS 42.9%), whereas uniform dose escalation to 74 Gy did not improve survival. RT-related lymphopenia is frequent and prognostic; reducing low-dose bath, minimizing exposure to iOARs, and optimizing target selection may preserve immune competence. SBRT/SFRT integrations and TIL-based cellular approaches warrant prospective testing but remain investigational.

Conclusions: A dual-track algorithm—perioperative chemo-IO for operable IIIA and cCRT followed by durvalumab for unresectable IIIA/IIIB—remains the evidence-based standard. Refinements that prioritize immune preservation (iOAR-aware planning, limited-field and hypofractionated strategies) represent promising areas of investigation that should not compromise tumor control. In patients with oncogene-driven disease, targeted therapy should be considered. When surgical resection is performed, tissue acquisition for molecular profiling and, in the context of clinical trials, TIL expansion may support personalized treatment strategies. These investigational approaches require prospective validation.