Tackling the current dilemma of immunotherapy in extensive-stage small cell lung cancer: A promising strategy of combining with radiotherapy

Progress in the treatment of small cell lung cancer (SCLC) has been modest over the past decades until the advent of immune checkpoint inhibitors, which have redefined the standard first-line treatment for extensive-stage SCLC (ES-SCLC). However, despite the positive results of several clinical trials, the limited survival benefit achieved suggests that the priming and sustaining of immunotherapeutic efficacy are poor and further investigation is urgently needed. In this review, we aim to summarize the potential mechanisms underlying the limited efficacy of immunotherapy and intrinsic resistance in ES-SCLC, including impaired antigen presentation and limited T cell infiltration. Moreover, to tackle the current dilemma, given the synergistic effects of radiotherapy on immunotherapy, especially the unique advantages of low-dose radiotherapy (LDRT), such as less immunosuppression and lower radiation toxicity, we propose radiotherapy as a booster to enhance the immunotherapeutic efficacy by overcoming the poor priming effect. Recent clinical trials, including ours, have also focused on adding radiotherapy, including LDRT, to first-line treatment of ES-SCLC. Additionally, we also suggest combination strategies to sustain the immunostimulatory effect of radiotherapy, as well as the cancer-immunity cycle, and further improve survival outcomes.