The Contribution of Senescent Cells to Cancer Progression and Therapy

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Mutant p53 and FOXO4 in Triple-Negative Breast Cancer

Recent findings suggest that senescent cell pathways can be exploited for cancer therapy. In triple-negative breast cancers (TNBCs), mutant p53 acquires an altered conformation with novel oncogenic properties. It interacts with the transcription factor FOXO4 within promyelocytic leukemia (PML) nuclear foci, structures typically restricted to senescent cells.

Experimental data show that targeting this FOXO4–p53 axis with a FOXO4-directed senolytic results in selective cytotoxicity against TNBC cells, while sparing other breast cancer subtypes. In mouse models of metastatic breast cancer, this approach significantly reduced metastatic burden. These findings highlight that tumors driven by mutant p53 exhibit senescent-like features, positioning them as candidates for senolytic-based interventions.

FOXO4–p53 Interaction and Senotherapeutic Potential

FOXO4 plays a critical role in maintaining the survival of senescent cells by binding to p53, preventing it from triggering apoptosis. By disrupting this interaction, apoptosis can be reactivated in these cells. FOXO4-DRI, a cell-permeable derivative mimicking the FOXO4 p53-binding domain, competitively inhibits the interaction, thereby inducing selective apoptosis of senescent cells without harming non-senescent populations.

Novel molecules with similar functions, such as ES2, have been developed through computational design. In melanoma mouse models, ES2 combined with BRAF inhibition enhanced apoptosis, improved survival outcomes, and reduced senescent cell burden. These studies underscore the therapeutic promise of senolytic strategies in both age-related pathologies and malignancies.

Senescence-Inducing Therapies and Senolytic Combinations

Senescence-inducing treatments can suppress tumor progression by halting proliferation and enhancing immune recognition. However, residual senescent cells secrete pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). These factors can contribute to tumor progression, metastasis, and therapy resistance if not adequately cleared.

Strategies that combine senescence induction with senolytic agents aim to optimize treatment outcomes. Senescent cells may also be detected non-invasively using imaging modalities such as PET-CT with β-galactosidase tracers or by measuring circulating senescence-associated proteins and metabolites. These tools may support patient stratification and therapy monitoring.

The Dual Role of SASP in Tumor Biology

SASP secretion has both tumor-suppressive and tumor-promoting consequences. In the early stages, cytokines such as IL-1α, IL-6, and IL-8 reinforce growth arrest, recruit immune cells, and contribute to clearance of senescent tumor cells. Over time, however, SASP factors can remodel the extracellular matrix through matrix metalloproteinases (MMPs), stimulate angiogenesis via vascular endothelial growth factor (VEGF), and promote tumor invasion.

Additionally, SASP-driven reprogramming may enhance stemness traits in cancer cells, increasing their capacity for relapse and aggressive progression. Notably, oncogene-induced senescent cells may escape growth arrest through telomerase reactivation or WNT-dependent signaling, reinitiating tumor growth. Thus, SASP represents a context-dependent factor in cancer development and recurrence.

Immune Surveillance and Senolysis

Senescent tumor cells influence the tumor microenvironment through immune-modulating effects. In preclinical models, combining checkpoint blockade therapy with senescence induction has improved anti-tumor immunity. For example, PD-1 inhibition, when paired with pro-senescence treatments, enhanced CD8 T-cell infiltration and vascular remodeling, facilitating better delivery of chemotherapeutic agents.

These immune effects vary by tissue context. Lung cancers exhibit NK cell–driven surveillance, whereas pancreatic cancers rely more heavily on T cell–mediated mechanisms. The composition of SASP factors appears to contribute to these differences, emphasizing the need for tailored senotherapeutic approaches.

Chemotherapy, Radiotherapy, and Therapy-Induced Senescence

Conventional cancer therapies often induce senescence alongside apoptosis. At lower doses, chemotherapies such as topoisomerase inhibitors, platinum compounds, alkylating agents, and antimetabolites trigger DNA damage responses that drive senescence. At higher doses, apoptotic pathways dominate. Similarly, microtubule-targeting agents disrupt mitotic progression, leading to DNA damage–induced senescence.

Radiotherapy also induces persistent DNA damage responses, promoting both apoptosis and senescence. While beneficial for local tumor control, this can elevate the senescent cell burden in surrounding tissues, potentially contributing to long-term side effects. Understanding how therapy-induced senescent cells interact with immune surveillance and the SASP will be critical for improving treatment regimens.

Glioblastoma and the Tumor-Promoting Role of Senescent Cells

In glioblastoma (GBM) models, partial removal of senescent cells increased survival. RNA sequencing of tumors lacking senescent cells revealed upregulation of cell cycle pathways and reduced expression of SASP-associated growth factors and extracellular matrix regulators. These findings support the concept that persistent senescent cells can facilitate tumor progression in gliomas, while their elimination may improve disease outcomes.

Conclusion

Senescent cells occupy a paradoxical role in cancer biology. While they initially suppress tumor growth through proliferation arrest and immune activation, their long-term persistence fosters a pro-tumorigenic environment through SASP-driven remodeling, angiogenesis, and reprogramming of tumor cells. Advances in senolytic strategies, including disruption of FOXO4–p53 signaling and immune-mediated senescence clearance, offer new therapeutic opportunities. Future approaches will likely rely on carefully balancing senescence induction with targeted senolysis to maximize tumor suppression while minimizing recurrence and progression.

REFERENCES

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