Abstract
BACKGROUND AND OBJECTIVE: The historical management of resectable non-small cell lung cancer (NSCLC) has relied on surgical resection and adjuvant chemotherapy, an approach with unsatisfactory long-term survival due to high rates of recurrence and micrometastasis. This narrative review synthesizes the evidence for a paradigm shift to neoadjuvant immunotherapy, which administers systemic therapy prior to surgery to address both the primary tumor and subclinical micrometastatic disease. METHODS: A comprehensive review was conducted on PubMed, Embase, and Scopus, limited to English-language articles from 2018 to the present to ensure a focus on recent, pivotal Phase II and III randomized clinical trials. The search used keywords such as 'neoadjuvant immunotherapy', 'resectable NSCLC', and 'biomarkers' to identify relevant studies. KEY CONTENT AND FINDINGS: Initial immune checkpoint inhibitor (ICI) monotherapy trials established feasibility and efficacy. Large-scale phase III trials like CheckMate 816 and AEGEAN have since established neoadjuvant chemo-immunotherapy as the new standard of care, demonstrating significant improvements in pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). This has validated pathological response as a surrogate endpoint for long-term survival, which accelerates drug development. The review also highlights novel combinations like antibody-drug conjugates (ADCs) in trials such as NeoCOAST-2, which have shown high pathological response rates, and discusses the evolution of biomarkers from programmed death-ligand 1 (PD-L1) to the more dynamic circulating tumor DNA (ctDNA). CONCLUSIONS: Neoadjuvant immunotherapy has fundamentally transformed the treatment landscape for resectable NSCLC, establishing a definitive paradigm shift from conventional surgery-first approaches and becoming a foundational component of modern multidisciplinary care with a promising trajectory toward improved long-term outcomes and the realization of minimal residual disease (MRD) guided therapy. Challenges remain, including the need for better predictive biomarkers, optimized regimens, and management of surgical complexities.