Unraveling Tumor Microenvironment of Small-cell Lung Cancer: Implications for Immunotherapy

Small-cell lung cancer (SCLC) is an aggressive lung cancer subtype and its first-line treatment has remained unchanged for decades. In recent years, immunotherapy has emerged as a therapeutic strategy for tumor treatment, whereas, patients with SCLC exhibit poor overall responses to immunotherapy alone, which highlights the necessity for combinatorial approaches. The tumor microenvironment (TME), an integral component in cancer, is widely implicated in tumorigenesis and tumor metastasis. The interactions of various cells within TME shape the adverse conditions of the tumor microenvironment (characterized by hypoxia, nutrient restriction, and acidity) and are considered responsible for the modest therapeutic responses to immunotherapy. Several studies have suggested that adverse TME can regulate immune cell activation and function. However, the specific regulatory mechanisms and their implications on immunotherapy remain unclear. Thus, it is worth unraveling the characteristics of TME and its impact on antitumor immunity, in the hope of devising novel strategies to reinforce immunotherapeutic effects on SCLC. In this review, we firstly elaborate on the immune landscape of SCLC and the formation of three remarkable characteristics in TME, as well as the interaction among them. Next, we summarize the latest findings regarding the impacts of adverse TME on immune cells and its targeted therapy in SCLC. Finally, we discuss the ongoing trials in combination therapy and potential directions of SCLC therapy. Collectively, the findings combined here are expected to aid the design of trials for combining immunotherapy with therapy targeting the TME of SCLC.