Overcoming Immunotherapy Resistance in Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most lethal histologic subtype of lung cancer. It is characterized by rapid tumor growth and early metastatic dissemination, resulting in an extremely poor prognosis. The addition of immunotherapy to standard chemotherapy has led to a modest improvement in survival for patients with extensive-stage disease. However, the overall clinical benefit remains limited due to both primary and acquired resistance to immunotherapy. Indeed, the efficacy of immune checkpoint inhibitors is influenced by multiple factors, including tumor heterogeneity, an immunosuppressive tumor microenvironment, and intrinsic molecular characteristics of the disease. In recent years, active research has been conducted to identify and therapeutically overcome resistance mechanisms to immunotherapy, and accumulating suggestive evidence is lighting the way for new strategies for clinical management of patients with SCLC. In this review article, we summarize and discuss the substantial obstacle to immunotherapy clinical efficacy, with a particular emphasis on the published and ongoing clinical trials that investigated the potential strategies to overcome mechanisms of resistance to immunotherapy. Moreover, we report and discuss the new therapeutic approaches tested, especially the use of antibody-drug conjugates, bi-specific antibodies, adoptive cell therapies and combination strategies.