Neoadjuvant Therapy for Non‐Small Cell Lung Cancer: Recent Advances and Future Directions

ABSTRACT

Neoadjuvant therapy has become an integral component of the multidisciplinary management of resectable non–small cell lung cancer (NSCLC). The introduction of immune checkpoint inhibitors (ICIs) has transformed the perioperative treatment landscape by improving pathological response rates, reducing the risk of recurrence, and offering the potential for durable survival benefits. In recent years, multiple neoadjuvant strategies, including ICI monotherapy, chemoimmunotherapy, dual immune checkpoint blockade, and combinations with radiotherapy, anti‐angiogenic agents, or targeted therapies, have been actively investigated to further optimize treatment efficacy. Immune checkpoint inhibitors (ICIs) are reshaping neoadjuvant strategies for resectable NSCLC. LCMC3 confirmed the feasibility of ICIs monotherapy, while CheckMate 816 and NADIM demonstrated that ICI–chemotherapy combinations markedly improve major pathological response and survival outcomes. Emerging perioperative studies, including CheckMate 77 T and AEGEAN, further support the integration of immunotherapy into standard treatment paradigms. Radiotherapy enhances tumor immunogenicity and shows synergy with ICIs, as highlighted in PACIFIC and KEYNOTE‐799. Although clinical evidence for ICI–anti‐angiogenic combinations remains preliminary, their mechanistic rationale is strong. In EGFR‐ or ALK‐altered NSCLC, emerging data suggest that neoadjuvant targeted therapy and carefully selected immunotherapy‐based strategies may further improve disease control while delaying recurrence. Despite these advances, several challenges remain, including the paucity of long‐term survival data, discordance between pathological responses and clinical benefit, treatment‐related toxicities, optimal treatment sequencing, biomarker‐guided patient selection, and mechanisms of primary or acquired resistance. Advances in predictive modeling based on PD‐L1 expression, tumor mutational burden (TMB), radiomics, nomograms, circulating tumor DNA, and multi‐omics biomarkers, together with a deeper understanding of metabolic–immune crosstalk, are expected to facilitate precision perioperative immunotherapy. This review comprehensively summarizes current evidence regarding neoadjuvant immunotherapy strategies for resectable NSCLC, highlights pivotal clinical trial findings, discusses emerging combination approaches and predictive biomarkers, and outlines future research directions aimed at improving personalized treatment and long‐term patient outcomes.