Synergistic effects and clinical utilization of radioimmunotherapy for brain metastases from driver mutation-negative non-small cell lung cancer

Brain metastasis (BM) is a common complication of advanced non-small cell lung cancer (NSCLC). Although immune checkpoint inhibitors (ICIs) have demonstrated efficacy in treating NSCLC-BM, their clinical benefits are often limited. The combination of radiotherapy (RT) and ICIs has emerged as a promising strategy for overcoming these challenges. This review summarizes the current knowledge regarding the immune landscape of NSCLC-BM as well as the clinical evidence supporting and challenging the RT-ICI combination, and it provides an expanded mechanistic framework detailing how RT reshapes the tumor immune microenvironment. RT can enhance the antitumor immune response by disrupting the blood-brain barrier, reprogramming the tumor microenvironment, and improving immune cell infiltration. Clinical studies have supported the synergistic potential of RT and ICIs against NSCLC-BM, showing improved survival and progression-free survival rates. However, challenges such as resistance and toxicity remain, and further investigation is required to refine treatment strategies. We further discuss optimal RT fractionation and sequencing strategies, toxicity mitigation, including practical approaches for managing radiation necrosis, and emerging biomarkers that may guide personalized treatment. A clearer understanding of these biological and clinical interactions is essential to refine treatment algorithms and maximize the therapeutic potential of radioimmunotherapy in NSCLC-BM.