Cellular senescence in cancer: from mechanism paradoxes to precision therapeutics

Abstract

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, we propose future directions to harness senescence as a dynamic therapeutic target, offering transformative potential for cancer treatment.

Keywords: Cancer; Senescence; Therapeutic innovation.

Fig. 1

Molecular pathways of oncogene-induced senescence, SASP promote immune clearance, and DNA damage. Oncogenic signaling activation: Growth factors (EGF, PDGF, FGF) bind RTKs, activating RAS-GTP and downstream pathways including PI3K-AKT-mTOR and BRAF-MEK-ERK to drive proliferation. Metabolic changes (NAD+/NADH, TCA cycle) contribute to senescence establishment. SASP-mediated immune clearance: Senescent cells secrete SASP factors that recruit and activate immune cells (T cells, NK cells) for tumor cell elimination. DNA damage: DNA damage activates ATM/ATR-CHK1/2-p53-p21-RB and p16-RB pathways, leading to cell cycle arrest. Abbreviations: EGF Epidermal Growth Factor, PDGF Platelet-Derived Growth Factor, FGF Fibroblast Growth Factor, RTK Receptor Tyrosine Kinase, GRB2 Growth Factor Receptor-Bound Protein 2, SOS Son of Sevenless, RAS-GDP RAS Guanosine Diphosphate, RAS-GTP RAS Guanosine Triphosphate, PDH Pyruvate Dehydrogenase, MEK Mitogen-Activated Protein Kinase Kinase, ERK Extracellular Signal-Regulated Kinase, REV-ERB Reverse ErbA-related orphan receptor, RORE Retinoic Acid Receptor-Related Orphan Receptor Response Element, SASP Senescence-Associated Secretory Phenotype, ATM/ATR Ataxia Telangiectasia Mutated/ATM and Rad3-Related, CHK1/2 Checkpoint Kinase 1/2, CDK2 Cyclin-Dependent Kinase 2, RB Retinoblastoma Protein, E2F E2F Transcription Factor

Fig. 2

SASP in the tumor microenvironment. Senescent cells accumulate cytosolic DNA, which is detected by the DNA sensor cGAS, leading to the synthesis of the second messenger 2’3’-cGAMP. This activates the STING pathway, triggering downstream IKK signaling, ultimately promoting the nuclear translocation of NF-κB. NF-κB drives the expression of SASP-related genes, which encode pro-inflammatory cytokines, chemokines, and growth factors. The metabolic enzyme ACSS2 and the NAD+-dependent deacetylase SIRT1 modulate this process, while Trim26 regulates both NF-κB and cGAS-STING signaling. Additionally, PAICS, involved in de novo purine synthesis, contributes to the availability of ATP and GTP, further supporting SASP activation. Abbreviations: PAICS Phosphoribosylaminoimidazole Carboxylase and Succinyltransferase, AC Acetyl-CoA, cGAS Cyclic GMP-AMP Synthase, STING Stimulator of Interferon Genes

Fig. 3

Metabolic reprogramming in cancer cells. Glucose is taken up via GLUT1 and rapidly metabolized through glycolysis, with pyruvate converted to lactate by LDHA, even under aerobic conditions. Mitochondrial metabolism remains active, with pyruvate entering via PDH to generate acetyl-CoA for the TCA cycle, while glutamine is processed by GLS1 into α-KG to sustain energy and biosynthetic precursors. Citrate from the TCA cycle is exported to the cytoplasm and converted by ACLY into acetyl-CoA, fueling lipid synthesis through ACC, FASN, and SCD-a process regulated by SREBP and HIF-1α. The PI3K/AKT/mTOR signaling axis further drives metabolic reprogramming by enhancing glucose uptake, glycolysis, and lipogenesis. HIF-1α, stabilized under hypoxia, promotes angiogenesis (via VEGF). To adapt to nutrient scarcity, cancer cells upregulate transporters (ASCT2, MCT4) and alternative pathways such as glutaminolysis and lipid storage. Abbreviations: ACLY ATP Citrate Lyase, ASCT2 Alanine-Serine-Cysteine Transporter 2, GLUT1 Glucose Transporter 1, G6P Glucose-6-Phosphate, HK2 Hexokinase 2, PEP Phosphoenolpyruvate, PKM2 Pyruvate Kinase M2, LDHA Lactate Dehydrogenase A, MCT4 Monocarboxylate Transporter 4, ACC Acetyl-CoA Carboxylase, FASN Fatty Acid Synthase, SCD Stearoyl-CoA Desaturase, IRS Insulin Receptor Substrate, PIP2 Phosphatidylinositol 4,5-Bisphosphate, PIP3 Phosphatidylinositol 3,4,5-Trisphosphate, GLS1 Glutaminase 1, α-KG Alpha-Ketoglutarate, Srebp Sterol Regulatory Element-Binding Protein, VEGF Vascular Endothelial Growth Factor

Fig. 4

Immunosenescence and its role in promoting tumor progression and therapy resistance. Senescent immune cells accumulate in the tumor microenvironment, exhibiting features such as oxidative damage and T-cell dysfunction. The SASP from these cells drives chronic inflammation and further suppresses immune function. Immunosuppressive cell populations, including Tregs and MDSCs, expand through pathways such as IDO/kynurenine/AhR, creating an immunosuppressive milieu. Innate immunity is also impaired, with aberrant TLR signaling and reduced MHC-II expression on dendritic cells and neutrophils, limiting antigen presentation. These alterations collectively diminish cytotoxic T-cell responses, reduce immune checkpoint inhibitor efficacy, and lower T-cell diversity, fostering therapy resistance. SASP, senescence-associated secretory phenotype. Abbreviations: ROS Reactive Oxygen Species, Tregs Regulatory T cells, MDSCs Myeloid-Derived Suppressor Cells, IDO Indoleamine 2,3-Dioxygenase, AhR Aryl Hydrocarbon Receptor, TLR Toll-Like Receptor

Fig. 5

Chromatin remodeling mechanisms in cellular senescence and tumorigenesis. Histone Modification: Degradation of HDAC4 leads to increased H3K27 acetylation at enhancer/promoter regions, activating senescence-related genes. DNA Methylation: DNMT1/HDAC1-mediated promoter methylation of P62 suppresses autophagy, while SAM serves as the methyl donor. Non-coding RNA Regulation: The lncRNA GAS5 modulates transcription, mRNA stability, and translation of senescence/tumor suppressor-related genes through binding regulation and RNA interactions. Abbreviations: SAM  S-Adenosyl Methionine, DNMT1 DNA Methyltransferase 1, HDAC4 Istone Deacetylase 4, GR Glucocorticoid receptor

Fig. 6

Summary of main therapeutic strategy targeting senescence. Senolytics and senomorphics (e.g., dasatinib/quercetin, mGL392, DR5-CNV/DOX, navitoclax) directly eliminate senescent cells or suppress their harmful SASP secretions. Metabolic interventions (e.g., arginine deiminase/arginase, asparaginase, metformin, orlistat, nicotinamide mononucleotide, elesclomol) disrupt amino acid synthesis, glycolysis, and lipid metabolism and induce apoptosis. Immunotherapies (e.g., salinomycin, Ru(II) complex Ru2c, NAD + Boosters, PD-1/PD-L1 Inhibitors, IFN-γ/sPD-1-engineered BMSCs, flavonoids, polyphenols) enhance immune clearance of senescent cells. Epigenetic modulators (e.g., 5-azacitidine/decitabine, romidepsin/panobinostat, diallyl trisulfide) reprogram senescent cells via DNA methylation or histone acetylation. Lastly, TME remodeling agents (e.g., losartan, hyaluronidase/collagenase, tranilast, SB525334) modify TME to improve therapeutic access