Introduction
Cellular senescence is a stress-responsive state characterized by durable proliferative arrest, distinct chromatin remodeling, and an expansive secretory program. Within neoplastic ecosystems, senescent cells accumulate in primary and metastatic niches and can arise from oncogenic signaling, stromal stress, or exposure to genotoxic regimens in laboratory models. Although senescence curtails cell division, the associated secretome—commonly termed the senescence-associated secretory phenotype (SASP)—reprograms the tumor microenvironment through cytokines, chemokines, proteases, and growth factors that influence immune infiltration, vascular tone, matrix remodeling, and paracrine signaling.
A growing body of preclinical work indicates that senescence is neither uniformly suppressive nor uniformly permissive for tumor growth. Instead, its impact is highly context dependent, varying with driver mutations, tissue of origin, timing relative to oncogenic transformation, and the composition of local immune cell networks. This complexity has inspired two experimental strategies: (i) inducing a stable growth arrest (pro-senescence) to limit expansion, and (ii) eliminating senescent cells (senolysis) to mitigate SASP-driven protumor activities. The sections below synthesize mechanistic insights from recent studies, with emphasis on FOXO4–p53 interactions, SASP circuitry, therapy-induced senescence, and immune-mediated senolysis.
Rewired Transcriptional Nodes in Senescent Tumor Cells
Senescent states remodel transcriptional networks that interface with canonical oncogenic pathways. In certain triple-negative breast cancer (TNBC) models, mutant p53 has been observed to adopt conformations that localize within promyelocytic leukemia (PML) nuclear bodies and physically engage Forkhead box O4 (FOXO4). This spatial organization suggests a senescence-linked scaffold in which mutant p53 and FOXO4 co-occupy chromatin regions to influence survival programs. Such nuclear structures are enriched in senescent cells, implying that cancers bearing senescent features may expose liabilities unique to FOXO4-centered protein–protein interactions and the maintenance of viability under stress. These observations motivate biochemical mapping of PML–FOXO4–p53 assemblies and their downstream effectors, including JNK, p38, and cell-fate determinants tied to apoptotic competence.
SASP as a Bifunctional Microenvironmental Driver
SASP factors originate from NF-κB and C/EBPβ-driven transcription and are primed by IL-1α–dependent feed-forward loops and persistent DNA damage signaling. Early SASP outputs (e.g., IL-6/IL-8) can reinforce arrest and promote immune surveillance in vitro and in vivo, enhancing recruitment of NK cells and type-1-polarized lymphoid subsets that recognize senescent targets. Over time, however, matrix metalloproteinases, VEGF, CXCL1 and related mediators remodel extracellular matrices, stimulate angiogenic sprouting, and can potentiate invasion or stem-like traits in neighboring tumor cells. The net effect therefore shifts with temporal phase, cell identity, and stromal composition, underscoring the need for time-resolved proteomics and single-cell transcriptomics to deconvolute SASP trajectories and their paracrine consequences.
Targeting the FOXO4–p53 Interface: Senolysis as a Research Modality
FOXO4 can stabilize p53 within senescent nuclei, restraining p53-dependent apoptosis. Peptidic disruptors that mimic the p53-interaction domain of FOXO family members (e.g., FOXO4-DRI and related designs) have been used in experimental systems to displace p53 from FOXO4, thereby re-licensing apoptotic pathways selectively in senescent cells. In diverse tumor models, such senolytic probes preferentially reduce senescent cell burden over non-senescent counterparts and have been reported to lower metastatic readouts in TNBC mouse systems. Parallel in-silico-designed peptides (e.g., ES2) highlight a convergent principle: destabilization of senescent survival hubs can unmask intrinsic apoptotic sensitivity. These approaches enable mechanistic interrogation of how senescent subsets sustain viability and how their removal reshapes SASP composition, vascular cues, and immune cell access in experimental tumors.
Therapy-Induced Senescence (TIS) and Exposure Windows
Genotoxic and mitotic stressors frequently used in oncology research—topoisomerase inhibitors, platinum compounds, alkylating agents, antimetabolites, microtubule poisons, and ionizing radiation—can induce senescence in a dose- and context-dependent manner. Lower exposures favor durable arrest, whereas higher exposures shift toward apoptosis. TIS engages ATM/ATR–CHK cascades and p53–p21/RB checkpoints, establishing arrest but also initiating SASP programs. Because only a fraction of tumor cells may enter TIS in vivo-like models, residual proliferative cells coexist with senescent neighbors, creating paracrine landscapes that can either aid immune surveillance or, alternatively, foster invasion and relapse. These kinetics support combinatorial paradigms in which senescence-inducing regimens are temporally followed by senolytic interventions to limit long-term SASP-driven remodeling in laboratory settings.
Immune Surveillance and Senolysis Orchestrated by the SASP
SASP chemokines and adhesion cues (e.g., VCAM1 induction on endothelium, CCL5/CXCL1 gradients) can enhance trafficking of cytotoxic lymphocytes into tumor sites in preclinical systems. In KRAS/TP53-mutant models, pro-senescence interventions have been linked to improved vessel perfusion and augmented uptake of co-administered cytotoxics, consistent with SASP-mediated vascular remodeling. Importantly, the dominant immune effectors vary by tissue: NK-cell programs appear prevalent in pulmonary contexts, whereas cytotoxic T-cell infiltration has been highlighted in pancreatic models. These differences likely reflect tissue-specific SASP repertoires and baseline immune compositions, emphasizing that senescence-immune crosstalk must be interpreted through an anatomic lens.
Senescence-Associated Stemness and Escape from Arrest
Despite initial arrest, subsets of senescent tumor cells can re-enter the cell cycle under specific conditions, including restoration of telomerase activity or shifts in WNT signaling. Cells emerging from this state may exhibit heightened tumor-initiating potential and aggressive phenotypes in experimental systems, raising the possibility that incomplete senescence or delayed clearance helps select for adaptable clones. Transcriptomic analyses show enrichment of stemness programs in these escapees, with SASP factors acting upstream to reinforce WNT pathway activity. Consequently, precise timing of senolytic strategies—relative to senescence induction—may be critical to curtail selection for high-plasticity populations.
Biomarker and Imaging Readouts for Senescence Burden
Quantifying senescence in vivo-like contexts benefits from multimodal assays. Beyond SA-β-gal activity and p16/p21 expression, emerging tools include PET-based tracers for β-galactosidase (e.g., 18F-labeled analogs) and circulating signatures of SASP proteins or metabolites as non-invasive surrogates of senescence load. Longitudinal deployment of these readouts in animal models enables evaluation of pro-senescence–senolytic sequences, supporting data-driven optimization of exposure windows and mechanistic attribution of antitumor versus protumor effects related to senescent cell dynamics.
Tissue-Specific Consequences: Glioblastoma as a Case Example
In glioblastoma models, partial ablation of senescent subsets has been associated with extended survival endpoints, accompanied by modulation of pathways linked to Notch, mTORC1, EMT, angiogenesis, and immune signaling. Bulk and targeted analyses reveal downregulation of selected SASP factors (e.g., Ereg, Fn1, Plau, Timp1, Bmp2) following senescent-cell reduction, suggesting that even small senescent fractions can disproportionately shape microenvironmental behavior. These findings reinforce the notion that senescent cells can function as paracrine organizers in brain tumor niches and that their selective removal alters the trajectory of tumor–stroma interactions in experimental systems.
Conclusion
Senescent cells influence tumor ecosystems through arrest-reinforcing checkpoints, SASP-driven communication, and context-dependent interactions with vasculature and immune networks. Mechanistic studies highlight the FOXO4–p53 node as a senescence-specific survival conduit and support the use of targeted senolysis to probe causality in metastasis, vascular remodeling, and immune access. At the same time, TIS-associated plasticity and possible senescence escape underscore the need for time-structured, pathway-resolved investigation. Continued research integrating proteogenomics, imaging biomarkers, and immune profiling will be essential to disentangle when senescence constrains malignancy and when it potentiates progression—and to determine how sequential pro-senescence and senolytic strategies can be leveraged as experimental tools.
References
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- Putavet, Diana, et al. “Abstract P1-19-02: Repurposing the FOXO4 Senolytic against Triple-Negative Breast Cancer.” Cancer Research, 82(4_Supplement), 15 Feb. 2022, P1-19-02, 10.1158/1538-7445.sabcs21-p1-19-02.
- Salam, Rana, et al. “Cellular Senescence in Malignant Cells Promotes Tumor Progression in Mouse and Patient Glioblastoma.” Nature Communications, 14(1), 27 Jan. 2023, 441, 10.1038/s41467-023-36124-9.
- Sánchez-Díaz, Laura, et al. “Senotherapeutics in Cancer and HIV.” Cells, 11(7), 2022, 1222, 10.3390/cells11071222.
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