Integrated management of immunotherapy and radiotherapy for patients with metastatic non-small cell lung cancer: a narrative review of current landscape and future directions.

Abstract

Background and objective: Despite advancements in systemic therapy, metastatic non-small cell lung cancer (NSCLC) remains largely incurable. Immunotherapy, primarily immune checkpoint inhibitors (ICIs), has improved outcomes, but durable responses are confined to a subset of patients. Emerging preclinical and clinical evidence suggests that radiotherapy (RT) can potentiate antitumor immunity, transforming localized treatment into a systemic effect. This narrative review aims to synthesize current knowledge on the mechanisms and clinical applications of combining RT with immunotherapy for metastatic NSCLC, assessing its potential to improve survival.

Methods: A systematic search of PubMed was conducted to identify English-language articles published between January 2010 and December 2025 on immunotherapy combined with RT for metastatic NSCLC.

Key content and findings: This article comprehensively analyzes the synergistic mechanisms between RT and immunotherapy, including immunogenic cell death (ICD), enhanced antigen presentation, and modulation of the tumor microenvironment (TME). We critically review the clinical evidence for this combination across various disease settings: definitive treatment of the primary tumor, management of brain and adrenal metastases, and the novel strategy of multisite RT. Key considerations such as the optimal sequencing of therapies and the influence of RT dose/fractionation on efficacy and abscopal effects are discussed.

Conclusions: The integration of RT with immunotherapy represents a promising therapeutic paradigm for metastatic NSCLC, demonstrating encouraging efficacy, particularly in managing thoracic disease and brain metastases. Preliminary data on targeting multiple metastatic sites are also compelling. However, critical questions regarding optimal patient selection, treatment sequencing, and ideal RT protocols remain areas of active investigation, necessitating further validation in randomized controlled trials.