Unraveling autophagy-metabolism crosstalk in cancer: Molecular insights and therapeutic strategies

Autophagy is a catabolic process essential for the degradation and recycling of damaged proteins and organelles, thereby contributing to the maintenance of cellular homeostasis and the integrity of the intracellular environment. Although autophagy serves protective physiological functions, its involvement in various diseases, particularly cancer, is complex and context-dependent. In the context of tumor development, autophagy plays two distinct roles. During the early stages of tumorigenesis, it functions as a tumor suppressor by preserving genomic stability. In later stages, however, it promotes tumor growth, supports the survival of cancer cells, and contributes to therapeutic resistance. Cancer cells are known to change their metabolic processes to support growth and division. Autophagy and metabolism work together, enabling cells to utilize both external and internal resources to generate energy and synthesize new molecules. This interaction is especially important in the stressful environment of tumors, like when there's not enough food or oxygen. In these situations, autophagy helps the tumor adapt metabolically and grow by breaking down and reusing parts inside the cell. In this review, we systematically examine the role of autophagy as a key regulator that coordinates diverse metabolic programs in cancer cells. We focus on central metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, as well as emerging regulatory networks involving nucleotide metabolism and mitochondrial metabolism. Importantly, we highlight how these metabolic pathways are dynamically integrated through autophagy to facilitate tumor adaptation, support metabolic plasticity, and drive therapeutic resistance.