Cellular senescence in cancer: from mechanism paradoxes to precision therapeutics

作者：Tiejun Feng, Fuda Xie, Leo Man-Yuen Lee, Zhiqiang Lin, Yifan Tu, Yang Lyu, Peiyao Yu, Jialin Wu, Bonan Chen, Ge Zhang, Gary M. Tse, Ka‐Fai To, Wei Kang · 发表于：Molecular Cancer · 年份：2025 · DOI：10.1186/s12943-025-02419-2 · 被引用次数：47 · 研究领域：Epigenetics and DNA Methylation、Telomeres, Telomerase, and Senescence、Immune cells in cancer

Cellular senescence is a double-edged sword in cancer biology, functioning as both a tumor-suppressive mechanism and a driver of malignancy. Initially, senescence acts as a protective barrier by arresting the proliferation of damaged or oncogene-expressing cells via pathways such as oncogene-induced senescence and the DNA damage response. However, persistent senescence-associated secretory phenotype and metabolic reprogramming in senescent cells create a pro-inflammatory, immunosuppressive tumor microenvironment, fueling cancer progression, therapy resistance, and metastasis. This comprehensive review systematically examines the molecular mechanisms of senescence across diverse cancers, spanning digestive, reproductive, urinary, respiratory, nervous, hematologic, endocrine, and integumentary systems, and elucidates its context-dependent roles in tumor suppression and promotion. We highlight groundbreaking therapeutic innovations, including precision senolytics, senomorphics, and combinatorial strategies integrating immunotherapy, metabolic interventions, and epigenetic modulators. The review also addresses microenvironment remodeling and cutting-edge technologies for dissecting senescence heterogeneity, epigenetic clocks for biological age prediction, and microbiome engineering to modulate senescence. Despite their promise, challenges such as off-target effects, biomarker limitations, and cellular heterogeneity underscore the need for precision medicine approaches. Finally, w...