Immunotherapy for extensive-stage small cell lung cancer: current status, challenges and future strategies

Abstract

Small cell lung cancer (SCLC) is characterized by rapid progression, early metastasis, and poor prognosis, with a five-year survival rate of less than 7%. In recent years, advances in immunotherapy, particularly the application of immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for extensive-stage SCLC (ES-SCLC) and led to modest improvements in patient survival outcomes. However, the immunologically "cold" tumor microenvironment (TME) and pronounced heterogeneity of SCLC drive resistance, limiting durable benefit. This unmet clinical need highlights the importance of developing novel strategies to extend and enhance treatment responses. Recent translational advances have accelerated the development of next generation of therapeutic approaches, including cellular therapies, multi-agent immunotherapeutic regimens, targeted modulation of the TME, antibody-drug conjugates (ADCs), cancer vaccines, and novel immunomodulatory agents, which hold promise for overcoming current limitations. This review summarizes current progress in immunotherapy for ES-SCLC, elucidates resistance mechanisms at molecular, cellular, and microenvironmental levels, and evaluates emerging therapeutic approaches with translational potential. By integrating mechanistic insights with clinical innovation, we highlight future directions toward biomarker-guided, personalized strategies that may ultimately transform ES-SCLC into a disease with more durable survival outcomes.

Keywords: Combination immunotherapy; Emerging therapies; Immunotherapy resistance; Small cell lung cancer; Tumor heterogeneity; Tumor microenvironment.