Immunometabolic reprogramming in lung cancer: interplay between immune and stem-like cells in immune checkpoint inhibitor resistance

Lung cancer remains the leading cause of cancer-related death worldwide. Despite the success of immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1 pathways, a significant number of patients exhibit either primary resistance or acquire resistance over time. While genomic and epigenetic mechanisms contribute to this resistance, increasing evidence points to the pivotal role of immunometabolism—the interface of cellular metabolism and immune regulation. This review focuses on how altered metabolic states in both immune cells and cancer stem-like cells (CSCs) within the lung tumor microenvironment contribute to ICI resistance. We discuss key metabolic pathways involved in immune suppression, the metabolic plasticity of CSCs, and how these factors interact to shape a metabolically hostile tumor niche for immune effector cells. Finally, we explore emerging therapeutic strategies targeting immunometabolism to enhance immunotherapy efficacy in lung cancer.