Under normal physiological conditions, timely removal of SnCs is important for tissue health and overall organismal homeostasis, while their accumulation can contribute to inflammaging and age-related disease. Although cellular senescence is an important tumor suppressive mechanism that limits the proliferation of damaged cells, it can paradoxically become an adversary in cancer treatment. Persistent SnCs within the TME promote a chronic inflammatory state that incites tumorigenesis and tumor growth and dampens anti-tumor immunity, exacerbating the adverse effects of cancer therapies [
17,
219]. The detrimental roles of senescence are linked to therapy resistance, metastasis, relapse, and poor treatment outcomes. Strategies that modulate the effects of the SASP or to eliminate these unwanted SnCs are being explored as avenues to enhance cancer therapies.
5.1. Malignant Transformation and Tumor Growth
SnCs in the stroma are increasingly implicated in cancer initiation and progression. Compared to pre-senescent fibroblasts, co-injecting neoplastic cells with senescent fibroblasts significantly increases tumor formation and growth rates, which suggests SnCs may create a niche that favors cancer development [
220]. Similarly, non-malignant epithelial cells exposed to senescent fibroblasts display changes indicative of invasive behavior and early malignant transformation, such as increased migration and nuclear atypia [
221,
222]. The elimination of SnCs through targeting of p16
INK4a-positive cells in transgenic INK-ATTAC mouse models has demonstrated a reduction in age-related tumorigenesis, further supporting the direct link between senescence accumulation and cancer risk [
223]. This effect is observed irrespective of the initial senescence trigger, reinforcing the broad nature of SnC-related growth promotion [
220,
224].
Conditioned medium from SnCs can confer growth advantages on non-senescent recipient cells [
221,
222], implicating SASP factors as contributors to SnC-related growth acceleration. For example, amphiregulin (AREG), promotes cancer cell proliferation and survival via paracrine activation of the epidermal growth factor receptor (EGFR) pathway in nearby cells [
225]. Senescent mesenchymal cells release IL-6, which can drive Stat3 signals and subsequent carcinogenesis by enhancing transformation, proliferation, and invasion. Depleting IL-6 in these SnCs can significantly reduce their ability to stimulate the proliferation and migration of neighboring breast tumor cells [
226]. Inhibiting the cGAS-dependent SASP in senescent fibroblasts similarly diminishes their capacity to support tumor growth [
224]. Other SASP factors, such as osteopontin and matrix MMPs, have also been implicated in promoting cell proliferation and cancer progression [
221,
227,
228].
5.2. Metastasis
SnCs can contribute to metastasis by promoting the migration, invasion, and extravasation of cancer cells as well as serving as a pre-metastatic niche. As an example, breast cancer cells implanted along with HER2-induced SnCs exhibit a marked increase in metastatic capability via non-cell autonomous mechanisms [
229]. This enhancement of metastatic potential is also observed following chemotherapy, where TIS in stromal cells and fibroblasts creates a nurturing environment conducive to tumor colonization in distant organs such as the liver, lungs, and bones [
230].
The pro-metastatic effect of senescence is largely attributed to the SASP. The conditioned medium from senescent fibroblasts formed by treatment with bleomycin alters breast cancer cell morphology and migration, advancing them to an aggressive state by affecting microtubule stability and dynamics [
231]. Senescent colon cancer cells treated with Fluorouracil also display a SASP that induces epithelial-to-mesenchymal transition (EMT) and enhances tumor cell invasion [
232]. Specific SASP factors may play predominant roles in these pro-metastatic effects. CXCL12 in BRAF
V600E-induced senescent thyrocytes is essential for their ability to promote thyroid carcinoma cell invasion [
233]. IL-6 secreted by senescent osteoblasts contributes to increased osteoclast genesis and bone metastases [
234]. MMP-1 and MMP-2 produced by senescent fibroblasts can promote skin carcinoma cell migration and keratinocytes EMT [
235]. Chemerin, a newly identified SASP factor, boosts the migration of cutaneous squamous cell carcinoma cells by activating the MAPK signaling pathway [
236].
SnCs influence vascular structure remodeling that further facilitates tumor metastasis. Co-transplantation of senescent thyrocytes with thyroid cancer cells has been shown to promote the development of lymphatic vessel networks and metastatic foci in lymph nodes [
233]. Additionally, senescent melanoma cells secrete SFRP2, a Wnt antagonist that stimulates angiogenesis and accelerates melanoma metastasis [
237]. Other SASP factors implicated in angiogenesis include vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) [
238,
239]. Suppressing the SASP through anti-inflammatory agents like Metformin has been shown to reduce pathological neovascularization driven by senescence, offering a potential strategy for mitigating cancer metastasis [
240].
5.3. Therapy Resistance and Cancer Stemness
The accumulation of SnCs within tumors is identified as a significant mechanism underlying therapy resistance. For instance, Doxorubicin-induced senescent endothelial cells in the thymus contribute to a chemo-resistant microenvironment. This niche supports the survival and eventual relapse of residual cancer cells, facilitated by the release of SASP factors such as IL-6 and Timp-1 [
241]. It has been observed that IL-6 secreted by senescent endothelial cells via PI3K/AKT signaling pathways is sufficient to confer chemoprotective effects [
242]. In breast cancer, p53-dependent senescence shields cancer cells from apoptosis via the SASP, consequently reducing the efficacy of Doxorubicin [
243]. The SASP released by Ras-induced senescent mesothelioma cells activate Stat3 signaling in neighboring cells and fosters the development of an EMT-like, clonogenic, and chemo-resistant subpopulation of cancer cells [
244].
Senescence may also contribute to stemness, which furthers tumor recurrence and therapy resistance. Ectopic expression of Yamanaka factors (OCT4, SOX2, KLF4, and cMYC) in mice paradoxically leads to both cell reprogramming and senescence [
245]. Key components of the senescence machinery, including p16
INK4A, p21
CIP1, p53, and H3K9me3, have complementary roles as regulators of stemness [
246]. Inhibiting SASP factors such as IL-6 can reduce cell de-differentiation, indicating that SnCs may enhance cellular plasticity via paracrine effects [
247]. RAS
G12V-induced SnCs can secrete a Stat3-dependent SASP that leads to the development of a subpopulation of progenitor-like cancer cells that exhibit resistance to chemotherapy agents like pemetrexed [
244]. Doxorubicin-induced senescence in liver cancer increases the expression of genes associated with reprogramming and liver stemness, including c-MYC and EpCAM, as well as the multidrug resistance gene ABCG2 [
248]. This enables adjacent tumor cells to upregulate tumor-initiating capabilities [
248]. Exposure of breast cancer MCF-7 cells to conditioned medium from SnCs or to key SASP factors like IL-6 and IL-8 induces stemness characteristics such as elevated CD44 expression and self-renewal capabilities [
249]. The senescence-mediated promotion of tumor cell reprogramming extends to hematological malignancies as well. DNA damage-induced senescent myeloma cells facilitate the emergence, sustenance, and migration of stem-like cancer cells through a CHK2-dependent SASP [
250]. Evidence also points to senescence playing a role in cancer stemness in B-cell lymphoma, B-cell chronic lymphocytic leukemia (B-CLL), and acute myeloid leukemia (AML) [
246].
5.4. Senescence Suppresses Anti-Immunity and Strategies to Overcome Senescence-Mediated Immunosuppression for Improved Cancer Treatment
Cellular senescence has been implicated in dampening immune responses (
Figure 3 and
Table 3). Systemic IR-induced senescence compromises the phagocytic capabilities of DCs and macrophages, thereby diminishing the proliferation of splenic B and T cells. Studies have demonstrated that targeted elimination of SnCs in the p16-3MR mouse model effectively restores the function of antigen-presenting cells (APCs) and leads to the rejuvenation of both T and B cell populations [
251]. The removal of p16
INK4-high senescent malignant cells similarly boosts T cell infiltration and reduces tumor-promoting macrophages in glioblastoma, thereby aiding in tumor suppression and enhancing survival rates in tumor-bearing mice [
252].
The SASP contributes to immunosuppressive effects mediated by SnCs. In prostate tumors lacking PTEN and treated with Docetaxel, SnCs exhibit sustained Jak2/Stat3 activation that induces an immunosuppressive SASP, leading to the accumulation of suppressive myeloid cells while depleting CD4
+, CD8
+, and NK cells. Genetically or pharmacologically inhibiting Jak2/Stat3 triggers a robust anti-tumor immune response and re-sensitizes tumors to Docetaxel [
253]. Conditioned medium from p27
Kip-driven senescent fibroblasts encourages the differentiation of bone marrow stem cells into CD11b
+Ly6G
Hi myeloid-derived suppressor cells (MDSCs), suppressing cytotoxic immunity and fostering a pro-tumorigenic environment. Neutralizing IL-6 from these fibroblasts reduces MDSC levels, reactivates T cell function, and delays tumor progression [
254]. Injection of Palbociclib-induced senescent fibroblasts also leads to MDSC infiltration through NF-kB pathways and accelerates melanoma growth in immunocompetent hosts [
255]. Interestingly, tumor-infiltrating MDSCs can antagonize senescence by secreting IL-1RA that blocks IL-1α-mediated OIS in neighboring cells, further impacting the overall efficacy of cancer treatment. Treatment with a CCR2 antagonist greatly reduces Gr-1
+ myeloid cell infiltration, improving chemotherapy in PTEN-null prostate cancer [
256]. In hepatocellular carcinoma, CCL2 secreted by N-Ras
G12V-induced senescent hepatocytes disrupts the maturation of CCR2
+ myeloid precursors. As a result, these immature myeloid cells efficiently suppress NK cell activity and significantly facilitate tumor progression [
257].
Notch signaling also emerges as a key regulator of immunosuppressive functions of SnCs. Elevated Notch signaling in N-Ras
G12V-induced senescent hepatocytes leads to a TGF-β-enriched SASP, which dampens T cell-mediated immune surveillance [
157]. Radiation-induced senescence in the lung similarly fosters a pro-tumorigenic microenvironment, characterized by increased neutrophil infiltration and amplified Notch signaling, with Notch inhibition markedly reducing radiation-enhanced metastases [
258]. Under hypoxic conditions, TGF-β can trigger senescence by repressing E2F targets and inducing a SASP that creates an immunosuppressive environment, which results in elevated myeloid cells and diminished immunotherapy success [
259]. Consequently, knockout of TGF-β receptors in lung cancer cells alleviates the senescence phenotype and restores immune balance [
259]. In colorectal cancer, senescent tumor cells driven by oxidative stress upregulate CXCL12 and CSF1 secretion. Increased levels of CXCL12 lead to reduced CXCR4 expression on CD8
+ T cells and inhibit their chemotactic migration. CSF1 promotes M2 macrophages differentiation that further impedes CD8
+ T cell activation. CXCL12/CSF1 neutralization therefore increases T cell infiltration and the efficacy of anti-PD-1 treatment [
260].
Metabolites secreted by SnCs can also contribute to immune suppression. Senescent hepatic stellate cells (HSCs) induced by obesity-associated gut microbe upregulate their production of prostaglandins (e.g., PGE2) via TLR2 signaling. The increase in PGE2 promotes regulatory T cells (Tregs) in the liver and diminishes cytotoxic T cell activity. Blocking the PGE2 receptor PTGER4 rejuvenates the anti-tumor immunity by elevating CD103
+ DCs and CD8
+ T cells while reducing Tregs, thus protecting against hepatocellular carcinoma induced by a high-fat diet [
261].
In addition to immunosuppressive effects of the SASP, senescent dermal fibroblasts display increased surface expression of the non-classical MHC molecule HLA-E that contributes to immunosuppressive effects by activating the NKG2A-mediated inhibitory pathway in NK and CD8
+ T cells [
262]. HLA-E induction can be amplified by IL-6 in both cell autonomous and non-autonomous manner. Blocking the interaction between HLA-E and NKG2A enhances immune surveillance of SnCs
in vitro, offering a strategy to alleviate senescence-associated immunosuppression [
262]. Additionally, SnCs regardless of DNA damage induced can upregulate the immune checkpoint molecule PD-L1, leading to CD8
+ T cell inhibition [
263,
264]. The mechanisms behind PD-L1's upregulation include enhanced E2F1 and/or NF-kB-mediated transcription, reduced proteasome activity, and cGAS-STING-driven paracrine effects [
263,
264,
265]. Studies on aging have revealed that anti-PD-1 treatments enhance immune surveillance of SnCs and reduce age-related dysfunctions in mice [
263]. Similarly, combining senescence-inducing chemotherapy, like Mitoxantrone, with anti-PD-1/PD-L1 therapies leads to tumor regression via cytotoxic T cells [
225]. SnCs induced by Doxorubicin or the CDK4/6 inhibitor Palbociclib upregulate PD-L2, another immune checkpoint receptor ligand that disrupts T cell function through PD-1 engagement and facilitates MDSC recruitment [
266]. Targeting this immunosuppressive mechanism with a PD-L2 blockade in combination with chemotherapy results in significant tumor reduction in murine syngeneic models [
266]. Such findings underscore the potential for immunotherapies to overcome SnC-induced immune suppression.
Figure 3.
Positive and negative effects of cellular senescence in the tumor microenvironment. Left, the anti-tumor effects of cellular senescence. Senescent cells contribute to anti-tumor defenses by facilitating the recruitment and activation of immune cells such as phagocytes (i.e., Mφ), dendritic cells (DCs), T cells, and natural killer (NK) cells. This is achieved through the SASP factors and surface proteins including class I MHC, NKG2D ligands, and ICAM-1. Activation of DCs by senescent cells provides an additional mechanism for cytotoxic lymphocyte-mediated tumor control. Senescence also plays a role in promoting angiogenesis, which contributes to the mobilization of immune cells to the tumor site. Beyond these immune-mediated actions, senescent cells contribute to the maintenance and spread of the senescent state through autocrine and paracrine mechanisms that suppress cell proliferation. Interleukin signals, particularly IL-1, are implicated in paracrine senescence. Right, the pro-tumor effects of cellular senescence. Senescent cells can dampen cytotoxic lymphocyte function by expressing certain surface molecules, including the non-canonical class I MHC molecule HLA-E and immune checkpoints PD-L1/2. Additionally, the SASP facilitates the recruitment and differentiation of immunosuppressive cells, like myeloid-derived suppressor cells (MDSCs) and M2-like macrophages, inhibiting NK and T cell function. Senescent cells may also contribute to tumor progression by promoting non-immunologic processes such as epithelial-mesenchymal transition (EMT), vasculogenesis, cancer cell reprogramming, malignant transformation, and hyperproliferation.
Figure 3.
Positive and negative effects of cellular senescence in the tumor microenvironment. Left, the anti-tumor effects of cellular senescence. Senescent cells contribute to anti-tumor defenses by facilitating the recruitment and activation of immune cells such as phagocytes (i.e., Mφ), dendritic cells (DCs), T cells, and natural killer (NK) cells. This is achieved through the SASP factors and surface proteins including class I MHC, NKG2D ligands, and ICAM-1. Activation of DCs by senescent cells provides an additional mechanism for cytotoxic lymphocyte-mediated tumor control. Senescence also plays a role in promoting angiogenesis, which contributes to the mobilization of immune cells to the tumor site. Beyond these immune-mediated actions, senescent cells contribute to the maintenance and spread of the senescent state through autocrine and paracrine mechanisms that suppress cell proliferation. Interleukin signals, particularly IL-1, are implicated in paracrine senescence. Right, the pro-tumor effects of cellular senescence. Senescent cells can dampen cytotoxic lymphocyte function by expressing certain surface molecules, including the non-canonical class I MHC molecule HLA-E and immune checkpoints PD-L1/2. Additionally, the SASP facilitates the recruitment and differentiation of immunosuppressive cells, like myeloid-derived suppressor cells (MDSCs) and M2-like macrophages, inhibiting NK and T cell function. Senescent cells may also contribute to tumor progression by promoting non-immunologic processes such as epithelial-mesenchymal transition (EMT), vasculogenesis, cancer cell reprogramming, malignant transformation, and hyperproliferation.
Table 3.
Immunosuppressive senescent cells in cancer.
Table 3.
Immunosuppressive senescent cells in cancer.
Senescence Induction methods |
Cancer type |
Affected immune cell population |
References (PMID) |
Doxorubicin |
Breast cancer |
SASP p16-3MR mice |
27979832 |
Docetaxel |
PTEN loss prostate cancer |
Increase Gr1+ MDSCs but decrease T and NK cells |
25263564 |
p27Kip1
|
Squamous cell carcinoma |
Increase CD11b+Ly6GHi MDSCs and Tregs |
27272654 |
Palbociclib |
Melanoma |
Promote the recruitment of Gr1+ MDCS |
28039358 |
Pten-loss |
PTEN loss prostate cancer |
Increase MDSCs |
25156255 |
N-RasG12V |
Liver cancer |
Increase MDSCs |
27728804 |
N-RasG12V
|
Liver cancer |
Reduce CD3+ T cells |
27525720 |
IR |
Lung metastases |
Promote Ly6G+ neutrophil recruitment |
35221334 |
TGF-β |
Lung cancer |
Increase infiltration of immune-suppressive cell types |
36821441 |
ROS |
Colorectal Cancer |
Enhance M2 macrophage polarization |
33643790 |
Metabolites (DCA and LTA) |
Hepatocellular carcinoma |
Suppress CD8+ T cells |
28202625 |
Mitoxantrone |
Prostate cancer |
Promote PD-L1 expression in tumors |
31493351 |
Doxorubicin |
Melanoma |
PD-L2+ senescent cells dampen T cell activity and promote of CD11b+Gr1+ MDSC recruitment |
38267628 |
H-RasG12V
|
Glioblastoma |
Decrease T cells and increase tumor promoting macrophages |
36707509 |
5.6. One-Two Punch" Therapies Using Senolytics against Cancer
Studies have demonstrated that the elimination of p16
high SnCs following Doxorubicin chemotherapy enhances breast cancer treatment response, reduces the likelihood of metastasis/relapse, and diminishes chemotherapy-associated toxicity [
219]. This approach suggests a potential pharmacological method to mitigate the negative impact of senescence by selectively targeting and eliminating SnCs using selectively toxic compounds, generally known as senolytics (
Table 4). Senolytics have shown considerable promise in addressing age-related diseases by eliminating naturally formed SnCs. In the context of cancer, they are often applied in a two-step strategy: initially inducing TIS within the tumor, followed by senolytic treatment targeting the vulnerabilities of the SnCs, referred to as the "one-two-punch" approach [
22].
Resistance to apoptosis in SnCs is notably modulated by elevated levels of anti-apoptotic Bcl-2 family proteins. Targeting Bcl-xL with siRNA has been a long-established approach to selectively eliminate SnCs while leaving proliferating or quiescent cells unaffected [
104]. BH3 mimetics, such as Navitoclax (ABT-263), which inhibits Bcl-xL, Bcl-2, and Bcl-w, can trigger apoptosis in SnCs effectively via a BAX/BAK-dependent mechanism that contributes to rejuvenation of accelerated or naturally aging mice and elimination of TIS [
73,
274,
275,
276]. Applying Navitoclax following the administration of senescence-inducing agents like Doxorubicin or Etoposide leads to substantial tumor suppression in both immune-deficient and -competent models [
277,
278]. Co-treatment with Navitoclax and Olaparib also displays synergistic effects on ovarian xenografts [
279]. Treatment with ABT-737, another Bcl-2 family inhibitor, removes the SnCs induced by K-Ras
G12D and minimizes the development of premalignant pancreatic lesions before their progression into PDAC [
280].
Although Navitoclax has been acknowledged as a potent senolytic agent in various preclinical studies, its clinical application is limited due to significant hematological side effects, including thrombocytopenia. To overcome this limitation, a galacto-conjugate of Navitoclax, Nav-Gal, has been developed. As a prodrug, Nav-Gal's senolytic potential is activated specifically within SnCs upon SA-β-gal cleavage [
281]. Nav-Gal can delay tumor progression when combined with Cisplatin [
281]. Nav-Gal also parallels Navitoclax in its ability to inhibit lung metastases in a mouse TNBC model, an outcome attributed to the elimination of SnCs induced by Palbociclib from lung endothelial cells [
282].
Inhibitors that target specific Bcl-2 family members for eliminating SnCs vary in efficacy, reflecting the diverse role of different Bcl-2 family proteins in providing apoptosis resistance to SnCs. Bcl-xL degraders based on proteolysis-targeting chimera (PROTAC) technology and specific Bcl-xL inhibitors (such as A1331852 or A1155463) display potency in eliminating senescent cancer cells [
275,
283]. Conversely, the specific Bcl-2 inhibitor ABT-199 shows inconsistent senolytic activity across various models [
275,
276,
278,
279]. Nevertheless, ABT-199 can destroy IR-induced senescent sarcoma cells [
284]. When combined with the senescence inducers Palbociclib and Fulvestrant, ABT-199 also successfully induces apoptosis and enhances breast cancer responsiveness [
285]. The Mcl-1 inhibitor S63845 has been identified as another senolytic [
278,
286]. The sequential application of Docetaxel followed by S63845 effectively eliminates SnCs and suppresses the growth of prostate cancer. Notably, this combination treatment also revitalizes anti-tumor immunity by diminishing immunosuppressive cells and amplifying cytotoxic immune markers [
286].
Beyond agents directly targeting Bcl-2 family members or other survival factors, the best studied senolytic agents are Dasatinib and Quercetin (D+Q), which contribute to extended health and lifespan [
104,
287]. D+Q has shown potential in preclinical models for controlling age-associated conditions like pulmonary fibrosis and neurodegeneration [
288,
289]. When used separately, D and Q also demonstrate senolytic properties through targeting senescent ovarian cancer cells triggered by the PARP1/2 inhibitor Olaparib [
279]. Other flavonoid derivatives, such as Fisetin and GL-V9, have also been recognized as senolytics [
279,
290]. While the precise mechanisms of action are still being explored, it has been suggested that senolytic flavonoids may work by blocking Bcl-2 family proteins such as BCL-xL and elevating ROS levels [
290]. Despite these promising outcomes, D+Q does not appear to target Doxorubicin-induced senescent hepatocellular carcinoma [
291], indicating the need for context-specific applications of this therapeutic strategy.
Compounds such as the BRD4 inhibitor JQ1 and the degrader ARV825 have also emerged as potent senolytics by promoting autophagy-induced cell death. For instance, ARV825 enhances liver cancer therapy outcomes when combined with Doxorubicin [
292]. The mTOR inhibitor AZD8055 eradicates SnCs caused by the CDC7 inhibitor XL413, demonstrating a synergistic effect on combating liver cancer. The HDAC inhibitor Panobinostat targets genotoxic TIS primarily via downregulating Bcl-xL expression [
293]. Cardiac glycosides such as Digoxin, Digitoxin, and Ouabain, have also been discovered as potential senolytics [
294,
295]. SnCs exhibit increased susceptibility to the ferroptosis inducer RSL3 compared to non-senescent cells, likely attributed to elevated levels of cytosolic lipid peroxidation [
296]. Canagliflozin, an inhibitor of sodium–glucose co-transporter 2 (SGLT2), may indirectly reduce the senescence load induced by a high-fat diet in mouse adipose tissue through activating AMPK signaling and potentiating immune surveillance [
297]. These studies have expanded the spectrum of agents for one-two-punch therapy.
Except for small-molecule senolytics, innovative approaches have led to the development of senolytic peptides and cell-based therapies. For example, FOXO4-binding peptide E2 disrupts the interaction between FOXO4 and TP53, leading to reactivation of TP53 transcription that induces apoptosis in SnCs. This intervention has shown promise in eliminating SnCs associated with aging and early-stage melanomas [
298]. Furthermore, senolytic chimeric antigen receptor (CAR) T cells targeting a surface marker of SnCs, urokinase plasminogen activator receptor (uPAR), further extend mouse survival in lung adenocarcinoma models treated with a senescence-inducing regimen of Palbociclib and Trametinib [
20,
299]. These advancements highlight the dynamic and evolving landscape of senolytic therapy, aiming to refine cancer treatment strategies with improved outcomes and reduced toxicity.