How diverse therapeutic strategies reshape the tumor immune microenvironment in small cell lung cancer: from radiation to engineered immunotherapies.

Small cell lung cancer (SCLC) is an aggressive and immunologically "cold" malignancy characterized by profound immunosuppression and limited responsiveness to immunotherapy. Its tumor immune microenvironment (TIME) exhibits defective antigen presentation, suppressive cytokine signaling, and abnormal stromal-metabolic interactions that collectively restrict immune activation and promote tumor progression. Overcoming this immune-cold state is an urgent prerequisite for improving therapeutic efficacy and achieving durable responses in SCLC.Converting SCLC from an immune-cold to an immune-active state requires integrated therapeutic strategies that relieve immunosuppression, restore antigen presentation, enhance effector lymphocyte infiltration and function, and overcome metabolic and stromal barriers that shape the suppressive TIME. This review integrates mechanistic insights with emerging therapeutic strategies for remodeling the SCLC TIME, focusing on radiotherapy, immunomodulatory therapies, stromal-targeted therapies, epigenetic therapy, and engineered immunotherapy platforms such as delta-like ligand 3 (DLL3)-directed bispecific T-cell engagers, CAR-T and cytokine-armored cells, biological vector-based immunotherapies, and nano-immunotherapy platforms. These advances outline a translational framework for converting immune-cold SCLC into an immune-responsive disease and achieving durable immunotherapeutic efficacy.