Research progress on immune microenvironment and biomarkers of small cell lung cancer

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases. SCLC is characterized by rapid proliferation, early distant metastasis, high recurrence rate, and poor prognosis, with a 5-year survival rate of less than 7%. Immune checkpoint inhibitor (ICI)-based immunotherapy has been widely applied in SCLC clinical practice, including immunotherapy combined with chemotherapy as first-line therapy, tarlatamab (post-chemo/immunotherapy) and lurbinectedin (post-platinum chemotherapy) as later-line options for extensive-stage SCLC (ES-SCLC), and chemoradiotherapy (CRT) followed by consolidation of immune therapy for limited-stage SCLC (LS-SCLC). However, the efficacy of immune combination therapy in SCLC patients remains limited and studies confirmed that objective response rate (ORR) of first-line immunochemotherapy in advanced SCLC is approximately 60-70%, while the durable response rate remains only 10-20%. The main reason lies in the complex and heterogeneous immune microenvironment of SCLC, where a network of immunosuppressive factors orchestrates an immune-excluded or "cold" phenotype. With the development of genomics application in SCLC research, increasing data have revealed and validated the immune microenvironment features of SCLC. However, there is a lack of systematic reviews in this field. This review focuses on clinical translational research across SCLC stages and subtypes, systematically summarizing the immune microenvironment features of LS-SCLC, ES-SCLC, recurrent/relapse SCLC, and never-smoker SCLC (nsSCLC) by integrating data generated from genomic sequencing, single-cell sequencing, spatial transcriptomics, and other research approaches. We summarize the biological and immune features of SCLC and highlight key biomarkers, with the goal of offering new perspectives to improve immunotherapy outcomes and uncover novel therapeutic vulnerabilities.