Aging‐Derived Alterations in Genomic, Immune, and Metabolic Networks: Implications for Cancer Development and Therapy

ABSTRACT Aging is the most potent independent risk factor for cancer initiation and progression, with these processes interacting through complex multi‐level biological networks. While current research has identified key pathways, systematic integration of their synergistic effects and actionable clinical strategies remains underexplored. This review examines the complex nonlinear relationship between age and cancer risk, focusing on immune‐cancer imbalance and late‐stage rebalancing phenomena that accompany aging. It introduces the novel concept of premature cancer, emphasizing its distinct molecular features and microenvironment. During aging, genomic instability, dysregulated epigenetic modifications, immune senescence, and metabolic reprogramming are key biological changes that destabilize the aging‐associated tumor microenvironment, fostering conditions conducive to cancer initiation and progression. The paper further explores the gene‐immune‐metabolic regulatory network formed through multidimensional interactions of these mechanisms, shedding light on how aging promotes cancer through this network. Additionally, translational therapeutic strategies, such as senescent cell eliminators and immunometabolic interventions, are discussed, with attention to challenges like the toxicity of senescent cell eliminators, the double‐edged sword effect of nicotinamide adenine dinucleotide (NAD⁺) supplementation, and treatment resistance. This work provides new insights for precision prevention and treatment of age‐related cancers, offering a foundation for advancing mechanistic research and promoting aging.