Neoadjuvant immunotherapy for non-small cell lung cancer: Opportunities and challenges

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.