Deciphering the nexus of aging and pan-cancer: Single-cell sequencing reveals microenvironmental remodeling and cellular drivers

Abstract

Aging constitutes a major risk factor for pan-cancer development, with epidemiological studies indicating that 60% of new malignancies occur in adults age 65 and older. This review synthesizes cutting-edge insights from single-cell sequencing databases (e.g., TCGA and GEO) that decipher how aging reprograms the tumor microenvironment (TME) to fuel carcinogenesis. Single-cell RNA sequencing (scRNA-seq) has revealed that senescent cell subpopulations (e.g., CDKN2A⁺/LMNB1^- cells) accumulate in aged tissues at frequencies up to 15%, driving genomic instability and secrete pro-tumorigenic senescence-associated secretory phenotype (SASP) factors (IL-6 and TGF-β). These factors remodel the TME by inducing fibroblast activation and extracellular matrix degradation, accelerating metastasis by 40-70% in murine models. Crucially, immunosenescence diminishes anti-tumor immunity, with scRNA-seq profiling showing 40-60% increases in exhausted PD-1⁺ T cells and immunosuppressive myeloid cells in aged TMEs. Pan-cancer analyses have identified conserved aging gene signatures (e.g., p16INK4a upregulation in 12+ cancer types) that correlate with 30-50% poorer survival. While technical challenges persist — including batch effects in scRNA-seq data and low senescent cell abundance (< 5%) — emerging solutions like deep learning can enhance detection sensitivity. Therapeutically, senolytic strategies deplete senescent cells, improving drug response by 3.5-fold in preclinical trials. Future research must integrate multi-omics and AI to examine aging-related targets, advancing personalized interventions for aging-associated malignancies.