Cancer therapy-induced senescence: A critical yet overlooked aspect

Cellular senescence, characterized by stable cell cycle arrest and the presence of the senescence-associated secretory phenotype (SASP), was initially recognized as a tumor-suppressive mechanism. However, recent research underscores its dual role in cancer biology and therapy. At sublethal doses, antitumor drugs, primarily intended to induce apoptosis or directly eliminate cancer cells, can also trigger cancer therapy-induced senescence (TIS). Radiotherapy (RT) is another potent inducer of TIS. Although TIS effectively halts cell proliferation and suppresses tumor growth, the SASP factors secreted by senescent cells (SCs) can significantly alter the tumor microenvironment (TME). These changes may promote tumor recurrence and metastasis while also exerting harmful effects on noncancerous cells, accelerating biological aging and compromising long-term treatment outcomes. The mechanisms underlying cellular senescence in cancer therapy are multifaceted Figure 1.Figure 1: Mechanisms of cellular senescence after tumor treatment. DDR: DNA damage response; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NK: Natural killer; p53: Protein p53; PI3K/AKT: Phosphatidylinositol 3-kinase/protein kinase B; SASP: Senescence-associated secretory phenotype; TME: Tumor microenvironment. This image was created using Adobe Illustrator.Tumor treatments induce DNA damage—either directly or indirectly—thereby activating a complex and coordinated DNA damage response (DDR). Although a DDR is essential to preserve genomic stability, its overactivation or dysregulation can paradoxically lead to errors during the repair process, resulting in incorrect base pairings, gene copy number alterations, and mutations, ultimately promoting genomic instability. In general, telomere attrition is a critical factor contributing to genomic instability. Current evidence suggests that TIS may not be directly related to telomere length but is instead associated with telomere dysfunction. The accumulation of ROS induced by TIS can cause telomere fragility, leading to cell-cycle arrest. Cell cycle regulation primarily involves modulating the expression of key genes and the activity of intracellular enzymes, proteins, and signaling factors. Major signaling pathways, such as protein 53 (p53), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), govern cell cycle progression by regulating the expression of target genes, proteins, or kinases within these networks. Additionally, the tumor-suppressor network functions as a vital defense mechanism that monitors and inhibits tumor formation. Following cancer treatment, tumor-suppressor genes such as p53 and retinoblastoma are activated in response to DNA damage or other cellular stressors. Activation of p53 leads to cell cycle arrest, allowing time for DNA repair or, in cases of severe damage, initiating apoptosis. Metabolic reprogramming, a hallmark of cancer, supports the energetic and biosynthetic demands of tumor proliferation by altering the metabolism of glucose, lipids, and amino acids. Mitochondria, which play a central role in cellular metabolism, are frequently reprogrammed during tumorigenesis. This mitochondrial dysfunction leads to elevated production of reactive oxygen species, which, in turn, damages key cellular processes, such as autophagy, and accelerates cellular aging. Epigenetic changes, including DNA methylation, histone modifications, and chromatin remodeling, regulate gene expression by altering chromatin structure without changing the underlying DNA sequence. Agents targeting epigenetic enzymes, such as DNA methyltransferase and histone deacetylase inhibitors, have demonstrated potential to promote senescence of cancer cells. For example, 5-azacytidine induces senescence by irreversibly binding to and inhibiting the activity of DNA methyltransferase 1. The SASP is induced by various factors secreted by SCs, including cytokines, chemokines, and growth factors. The TME—composed of stromal cells, neovascular structures, and immune components—is highly dynamic and interacts with SASP factors through both autocrine and paracrine signaling. Through these interactions, SASP factors can remodel the TME by accelerating secondary senescence of neighboring cells, promoting immune evasion, and facilitating tumor recurrence and metastasis. Cancer cell senescence: Antitumor treatments can lead to either tumor cell death or the induction of cellular senescence. SCs secrete various proinflammatory cytokines and chemokines, which recruit immunosuppressive cells into the TME, including myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages (TAMs). These cells secrete immunosuppressive cytokines, such as transforming growth factor-β (TGF-β) and interleukin (IL)-10, and express inhibitory immune checkpoint molecules, which collectively suppress antitumor immune responses. Macrophage senescence and TAM polarization are critical for the formation of an immunosuppressive TME. The senescent microenvironment drives the conversion of macrophages into TAMs. TAMs induce macrophage polarization toward an M2 protumor phenotype via the signal transducer and activator of transcription 3 (STAT3)/IL‑10 axis, and enhance the recruitment of immunosuppressive cells, thereby sustaining and exacerbating the immunosuppressive network. TIS also impairs the function of cytotoxic T lymphocytes. Studies have shown that chemotherapy alters macrophage–CD8+ T cell interactions in the TME, significantly affecting the functional state and promoting exhaustion of CD8+ T cells. Although CD8+ T cell infiltration increases following chemotherapy, these cells exhibit elevated levels of exhaustion markers, such as TIM-3, indicating a suppressed functional state. Drug resistance arises from a complex interplay of cancer cell-intrinsic and microenvironmental factors. Under therapy pressure, residual tumor cells—including senescent or senescent-like drug-tolerant populations—may exhibit enhanced drug efflux and metabolic adaptation. For instance, energy-dependent transporters such as MDR1 can reduce intracellular drug concentrations and contribute to treatment resistance. In parallel, hypoxia and nutrient limitation promote metabolic reprogramming (e.g., altered glycolysis, mitochondrial dysfunction, and lipid accumulation), which can support survival and persistence after treatment. The tumor microenvironment further reinforces resistance by impairing immune-mediated clearance, limiting drug uptake, and activating paracrine survival signaling. Following radiotherapy, resistant subpopulations with reduced antigen-presenting capacity and enhanced immune evasion have been reported, which may compromise immune elimination of residual cells.1 Most anticancer regimens are administered in cycles to allow recovery of normal tissues; however, these treatment-free intervals can also create a window for surviving tumor cells to persist, adapt, and repopulate. Importantly, therapy-induced senescent cells can remain viable during these intervals, and a subset of these cells may regain proliferative potential, re-enter the cell cycle, and upregulate stemness-associated genes, significantly contributing to tumor invasion and disease recurrence. Zhang et al2 investigated the effects of doxorubicin on breast cancer cells and found that co-culturing SCs and non-SCs resulted in a more pronounced epithelial–mesenchymal transition in the direct co-culture model as compared to the indirect model, wherein only conditioned medium from SCs was used. Several SASP components, such as IL-6, IL-1, and IL-8, can promote the recruitment of immune cells, including cytotoxic T lymphocytes, natural killer cells, and macrophages, thereby enhancing immune surveillance. However, persistent IL-6 secretion has been shown to upregulate human leukocyte antigen E, which subsequently suppresses the activities of natural killer cells and CD8+ T cells, thereby facilitating immune evasion. In addition, chemokine C-C motif ligand 2 (CCL2) recruits macrophages that intensify inflammatory responses and promote tumor growth through the secretion of factors, such as vascular endothelial growth factor A (VEGF-A). Persistent SASP cues may also reprogram stromal compartments; for instance, cancer-associated fibroblasts can secrete pro-invasive chemokines such as CCL5, and similar stromal remodeling has been observed after radiotherapy.3 Noncancer cellular senescence: Antitumor therapies induce not only tumor cell death and senescence but also widespread senescence of noncancerous or benign cell populations. In these normal cells, senescence is typically considered an adverse side effect of treatment, contributing to tissue dysfunction, systemic toxicity, and long-term complications. Studies have shown that RT and over 90% of chemotherapeutic agents can induce myelosuppression, primarily through the senescence of hematopoietic stem cell (HSCs) and mesenchymal stem cell (MSCs). HSCs possess the capacity for self-renewal and differentiation into various immune cell lineages; however, this self-renewal capability is not unlimited. HSCs harvested from aged donor mice exhibit significantly reduced self-renewal capacity when transplanted into young recipients, compared with those derived from young donor mice.4 MSCs exhibit strong multipotent and regenerative capabilities; however, these functions are significantly impaired in senescent MSCs. Senescent MSCs can exacerbate the effects of HSC senescence by secreting hematopoietic-inhibitory inflammatory cytokines that suppress normal hematopoiesis. Wang et al5 demonstrated that cyclophosphamide induces both myelosuppression and MSC senescence in mice. Additionally, Skolekova et al6 found that cisplatin-treated MSCs are resistant to apoptosis but exhibit senescence-associated phenotypes in mice, including secretion of high levels of IL-6, IL-8, and other cytokines, thereby enhancing chemoresistance and stemness of tumor cells while reducing responsiveness to chemotherapy in vivo. Antitumor treatments can also induce senescence of other noncancerous cell types—such as alveolar epithelial cells and cardiomyocytes—which is often associated with adverse effects and treatment-related complications. Nonhematologic adverse effects are commonly observed following the administration of traditional chemotherapeutic agents and may be closely associated with tissue-specific cellular senescence. Pulmonary toxicity is one of the most frequent adverse effects of bleomycin, strongly linked to the senescence of alveolar epithelial cells. If left untreated, bleomycin-induced pulmonary toxicity can damage the lung interstitium, impair gas exchange, cause dyspnea, and ultimately lead to respiratory failure and death. Similar pulmonary effects have also been observed following RT. Cardiotoxicity, a well-documented adverse effect of doxorubicin, is associated with the senescence of cardiomyocytes. Senescent cardiomyocytes not only experience intrinsic dysfunction, such as impaired contractility and abnormal conduction, but also induce senescence of neighboring cardiomyocytes through paracrine signaling. Renal damage is another significant side effect of doxorubicin. Tubular epithelial cells, which play a central role in acute kidney injury, are particularly vulnerable. Senescence of these cells disrupts renal repair mechanisms and promotes the secretion of SASP factors, thereby accelerating the transition from acute kidney injury to chronic kidney disease. The clinical application of tumor-targeted therapies has been established for only about five decades, however, investigations of potential adverse effects, particularly those associated with therapy-induced cellular senescence, remain limited. Emerging evidence indicates that sunitinib, palbociclib, and ponatinib can all induce senescence, which has been mechanistically linked to vascular toxicity, hypertension, and cancer progression. Senotherapeutics: In cancer therapy, the accumulation of SCs is generally considered detrimental. Senotherapy has emerged as a promising approach to mitigate aging and age-related diseases by selectively eliminating or modulating SCs. In addition, a novel therapeutic approach known as the “one-two punch” strategy is being introduced. The first punch involves the administration of therapeutic doses of anticancer drugs to induce tumor cell death while simultaneously triggering senescence of both tumor and normal cells. The second punch involves the elimination or modulation of SCs using senotherapeutic agents to prevent tumor recurrence, metastasis, and treatment resistance. This strategy holds significant promise to improve cancer treatment and manage aging-related conditions, offering new directions for future clinical applications. In conclusion, cellular senescence in cancer therapy stands at a pivotal turning point. Importantly, senescence of noncancerous cells has emerged as a key contributor to therapy-related toxicity. The identification of novel biomarkers for SC subtypes and context-specific SASP profiles may support the development of tailored senescence-targeted interventions. Moreover, incorporating senotherapeutics into existing treatment paradigms—such as the “one-two punch” model—holds promise to improve therapeutic efficacy and minimize relapse. Funding This work was supported by a grant from the Key Science and Technology Program of the Health Commission of Shanxi Province (2025ZD018). Conflicts of interest None.