Lipid Metabolic Reprogramming in Lung Cancer: Mechanisms and Therapeutic Targets in the Tumor Microenvironment

Lung cancer remains a leading cause of cancer-related deaths globally, with tumor progression and metastasis being heavily influenced by the dynamic interactions within the tumor microenvironment (TME). Lipid metabolic reprogramming, a recognized hallmark of cancer, plays a crucial role in these processes. However, a comprehensive understanding of how cancer cell-intrinsic lipid metabolism and its crosstalk with immune and stromal cells collectively drive tumor metastasis remains to be fully elucidated. This review synthesizes preclinical and clinical evidence to map the interconnected lipid metabolic networks spanning tumor, immune, and stromal compartments. It highlights how cancer cell-autonomous lipid metabolic reprogramming and its metabolic crosstalk with immune and stromal cells drive lung cancer progression and therapy resistance, thereby reshaping the TME into a pro-tumorigenic ecosystem. Furthermore, we provide an in-depth analysis of the potential of therapeutic strategies targeting these metabolic pathways, discussing both the opportunities for development and the challenges that lie ahead. By integrating the multifaceted roles of lipid metabolism in the lung TME, this review provides a novel perspective on tumor biology and aims to inspire future research directions for innovative combination therapies.