Convergence of immunometabolism and lung cancer therapy: redefining the tumor–immune interface

Abstract Surgery, chemotherapy, radiotherapy, and immune checkpoint blockade remain the mainstays of lung cancer treatment. Despite these approaches, lung cancer continues to be the second leading cause of cancer-related deaths worldwide. Recent insights into the metabolic reprogramming of lung tumors and their interplay with immune cells termed immunometabolism have revealed crucial mechanisms shaping tumor progression and therapeutic response. In lung cancer, T lymphocytes, natural killer cells, and macrophages undergo metabolic alterations that tumors exploit to create an immunosuppressive microenvironment, while tumor cells adopt metabolic switches that support growth, survival under stress, and evasion of immune surveillance. The dynamic regulation of glucose, oxygen, and amino acid availability in the lung tumor microenvironment influences T cell activation, macrophage polarization, and recruitment of immunosuppressive cells. Key oncogenic pathways, including c-Myc, HIF-1α, and PI3K–AKT–mTOR, coordinate these metabolic and immune adaptations. These insights have inspired novel therapeutic strategies that combine tumor metabolism-targeting with immune metabolism modulation to enhance antitumor immunity, often in conjunction with immune checkpoint blockade or adoptive cell therapy. Advances in single-cell and spatial metabolomics now enable precise characterization of metabolic heterogeneity in lung tumors, paving the way for personalized interventions exploiting immunometabolic vulnerabilities. This review emphasizes lung cancer-specific immunometabolism as a promising avenue for improving treatment outcomes, integrating molecular mechanisms, clinical trials, and emerging technologies.