Unraveling the nexus between cellular senescence and malignant transformation: a paradigm shift in cancer research

Cellular senescence, a natural process wherein cells cease division and undergo irreversible growth arrest, has long cap-tivated the curiosity of scientists because of its many implications in aging and disease. Recent research has shed light on the nexus between cellular senescence and malignant transformation, thus leading to a paradigm shift in understanding cancer development and progression. Senescence was initially recognized as a safeguard against tumorigenesis but is now understood to have more nuanced roles in tissue repair, embryonic development, and immune surveillance, thus highlighting the intricate and complex balance between aging and cancer. Clarifying the dual effects of senescence will be critical for understanding the fundamental biology of aging 1 . Elucidating the mechanisms through which senescent cells evade or succumb to malignant transformation should provide invaluable insights for the development of novel therapeutic strategies against cancer.

Cellular senescence, a natural process wherein cells cease division and undergo irreversible growth arrest, has long captivated the curiosity of scientists because of its many implications in aging and disease.Recent research has shed light on the nexus between cellular senescence and malignant transformation, thus leading to a paradigm shift in understanding cancer development and progression.Senescence was initially recognized as a safeguard against tumorigenesis but is now understood to have more nuanced roles in tissue repair, embryonic development, and immune surveillance, thus highlighting the intricate and complex balance between aging and cancer.Clarifying the dual effects of senescence will be critical for understanding the fundamental biology of aging 1 .Elucidating the mechanisms through which senescent cells evade or succumb to malignant transformation should provide invaluable insights for the development of novel therapeutic strategies against cancer.

Cellular senescence: guardians or instigators?
Cellular senescence is as a critical safeguard mechanism that maintains tissue homeostasis and prevents the unchecked proliferation of damaged or aberrant cells.Triggered by a myriad of stressors including DNA damage, telomere shortening, or aberrant oncogenic signaling, senescence prompts cells to enter a state of permanent growth arrest while retaining metabolic activity.Historically, cellular senescence has been considered to protect against cancer, by halting the proliferation of damaged or oncogene-driven cells and preventing their uncontrolled expansion 2,3 .Senescent cells undergo irreversible growth arrest accompanied by distinct morphological changes and the secretion of bioactive molecules known as the senescence-associated secretory phenotype (SASP).SASP components, including pro-inflammatory cytokines, growth factors, and matrix metalloproteinases, shape the tissue microenvironment, and consequently influence neighboring cells and immune surveillance via cell communication 4,5 .This intricate interplay underscores the multifaceted roles of senescent cells in modulating tissue homeostasis and immune responses.Moreover, the secretome and autocrine network of senescent cells expand the effects of senescence, by promoting senescence of these cells and their surrounding tissues 6 .
However, emerging evidence challenges the simplistic view of cellular senescence solely as a barrier to tumorigenesis (Figure 1).Senescent cells exhibit phenotypic heterogeneity, wherein subsets display a pro-tumorigenic secretome that promotes malignant transformation in neighboring cells.Strong evidence supports this view: senescent fibroblasts have been shown to directly promote the proliferation of precancerous or tumor cells in co-culture 7 .We have demonstrated that the deletion of sirt1, encoding an important molecule for homeostasis maintenance and anti-aging, aggravates the phenotypic transformation of SASP in stromal cells and enhances drug resistance mediated by the expression of ATP-binding cassette subfamily B member 4 (ABCB4) in cancer cells 8 .Recently, the mechanism through which TIMP1 deletion promotes tumor metastasis by activating MMP-mediated senescence reprogramming has been revealed 9 .Moreover, treatment-induced cell senescence within tissues can fuel chronic inflammation, thereby exacerbating tumorigenic processes, increasing the treatment of tumor resistance, and indicating that the pathological process of malignant transformation is more complex and elusive than previously understood [10][11][12] .
The dichotomous nature of cellular senescence prompts questions of whether these cells truly guard against cancer or whether they might potentially instigate malignant transformation under certain contexts.

Deciphering the molecular crosstalk: insights into malignant transformation
At the molecular level, the intricate crosstalk between senescence and malignant transformation forms a complex network of signaling pathways and regulatory mechanisms (Figure 2).Dysregulated signaling cascades, including the p53-p21 and p16INK4a-Rb pathways, orchestrate the induction and maintenance of cellular senescence in response to stressors as diverse as telomere attrition and oncogenic insults.We have found that haploid loss of TP53 rescues aging in BRCA1-null mice but is accompanied by elevated tumor incidence 3 .These findings imply a delicate balance, and a more complex relationship between life homeostasis maintenance and malignant transformation, than previously understood.The mechanism of intracellular homeostasis maintenance can be considered a "double-edged sword" that prevents malignant transformation at the expense of homeostasis 2,13 .
However, cancer cells have evolved sophisticated mechanisms to subvert these barriers, by exploiting vulnerabilities within the senescence machinery to fuel their aberrant proliferation and survival.The increase in somatic mutation rate with aging leads to the accumulation of pro-tumorigenic and pro-aging factors, and the population spread of positively selected mutated genes, such as TP53 and NOTCH1 14 .Mutated TP53 loses its important tumor suppressor function and is associated with the level of genomic hypomethylation 15 .Autophagy is an important cell survival mechanism in response to various stress conditions, including starvation, hypoxia, and mitochondrial damage, as presented in our work 16 .Our recent research has demonstrated that the ROS-ATM-CHK2 axis phosphorylates a variety of substrates, such as Beclin1, ULK1, and TRIM32, thereby promoting mitophagy in cancer cell lines [17][18][19] .In addition, a lactylation-dependent homeostatic maintenance mechanism of DNA damage has recently been identified 20 .These mechanisms further contribute to the homeostatic balance within tumor cells and exacerbate malignant transformation.
Notably, emerging studies have highlighted the roles of epigenetic alterations in orchestrating the transition from senescence to malignancy.Epigenetic reprogramming, encompassing changes in DNA methylation, histone modifications, and chromatin remodeling, can tip the balance toward a pro-tumorigenic phenotype within senescent cells.Previously, we reviewed the relationships among DNA methylation, maintenance of homeostasis, and malignant transformation 21 .Recently, we have focused on epigenetic modifications in the proteome.SIRT2-mediated deacetylation-phosphorylation of the SMC1A axis plays an important role in maintaining colon cancer genome homeostasis 22 .Aberrant expression of key transcription factors and non-coding RNAs further contributes to the rewiring of cellular identity, thereby fueling the emergence of senescence-associated pro-tumorigenic traits 23 .
Furthermore, the intricate interplay between senescent cells and the tumor microenvironment (TME) is a critical determinant of cancer progression.Senescent cells sculpt the TME through the secretion of SASP factors, thereby fostering a pro-inflammatory milieu conducive to tumor growth, angiogenesis, and metastasis.We have found that AREG secreted by senescent stromal cells induces the expression of programmed cell death 1 ligand (PD-L1) in recipient cancer cells, thus producing an immunosuppressive TME 24 .In contrast, immune surveillance mechanisms for eliminating senescent cells can be hijacked by cancer cells, thereby fostering immune evasion and tumor immune escape 8,24 .Recently, eIF5A has been found to be important in promoting the expression of SASP factors, maintaining the SASP phenotype, and consequently regulating immune surveillance 25 .Recent results have revealed that depletion of senescent cells in the TME can prolong patient survival and decrease tumor burden 26,27 .Thus, the dynamic interplay among senescent cells, cancer cells, and the TME dictates the trajectory of malignant transformation, and may reveal novel therapeutic targets and prognostic markers.

Therapeutic implications and future perspectives
The growing insights regarding the links between cellular senescence and malignant transformation have major implications for cancer therapy and intervention strategies (Figure 3).Therapeutic modalities aimed at selectively targeting senescent cells or modulating their secretomes are promising avenues for attenuating cancer progression and enhancing treatment efficacy 8,24 .Senolytic agents, which selectively induce apoptosis in senescent cells, have garnered considerable attention for their potential to alleviate senescence-associated pro-tumorigenic effects 28 .Furthermore, strategies aimed at reprogramming the senescence-associated secretome hold promise for mitigating its deleterious effects on the TME.Targeted inhibition of key SASP components or modulation of senescence-associated signaling pathways may offer therapeutic benefits, by dampening inflammation and restoring immune surveillance within the tumor milieu 29 .Additionally, harnessing the immune system to selectively target senescent cells through immunotherapeutic approaches is an intriguing avenue for combating cancer progression and improving patient outcomes 30 .
In the future, understanding the intricacies of the senescence-malignancy axis will require interdisciplinary collaboration and innovative methods spanning genomics, epigenomics, and systems biology.Integration of multi-omic datasets coupled with advanced computational modeling has the potential to decipher the complex regulatory networks governing senescence and malignant transformation, and to pave the way to precision medicine approaches tailored to individual patient profiles.

Conclusions
In conclusion, understanding the links between cellular senescence and malignant transformation has led to a paradigm shift in cancer research, by challenging conventional notions that senescence is a static barrier against tumorigenesis.As the multifaceted roles of senescent cells in shaping the TME and fueling cancer progression are revealed, novel therapeutic strategies are expected to emerge and offer new hope for cancer treatment.Harnessing the dynamic interplay between senescence, cancer cells, and the TME is expected to be the start of a transformative journey toward achieving personalized cancer therapy and precision medicine.

Figure 1
Figure 1 The dual roles of senescent cells in tumor development and progression.The occurrence of aging or therapeutic senescence has dual effects on tumor development and treatment.On the one hand, aging-mediated tumor cell growth arrest functions primarily as a tumor suppressor in early stages of tumor progression.Moreover, components secreted by senescent cells such as IL-6 and IL-8 reinforce the effects of senescence and further inhibit tumor progression (blue arrow).On the other hand, aging of the whole body mediates changes in the tumor environment, thereby aggravating tumor treatment resistance, tumor metastasis, angiogenesis, downstream metastasis, and early remodeling of the micro-environment (red arrow).Notably, senescent fibroblasts secrete components such as IL-6, L-8, AREG, CCL5, CXCL12, OPN, and HGF, which promote tumor cell proliferation, metastasis, and angiogenesis by remodeling the tumor microenvironment through MMPs and VEGF.In metastatic sites, senescent osteoblasts remodel the downstream metastatic microenvironment and promote the seeding and proliferation of circulating tumor cells.

Figure 2
Figure 2 Cell-fate decisions mediated by intricate molecular crosstalk.At the cellular and molecular levels, multiple signaling pathways and regulatory mechanisms are intertwined in a complex network.Dysregulated signaling cascades, such as the p53-p21 and p16INK4a-Rb pathways, lead to imbalances in the cellular senescence response to various stresses, thereby contributing to malignant transformation.Certain mutations have been shown to delay the aging process but also increase the risk of tumorigenesis.In the process of malignant transformation, cellular homeostasis maintenance mechanisms and epigenetic reprogramming play important roles.The maintenance mechanism of cellular homeostasis is not only key to maintaining biological homeostasis but also serves as barrier to preventing the malignant transformation of cells.However, cancer cells achieve aberrant proliferation and survival by exploiting the vulnerabilities of the aging machinery and escaping the restrictions of the maintenance mechanisms of cellular homeostasis.In addition, senescent cells alter the tumor microenvironment by secreting proinflammatory factors, which further contribute to tumor development and treatment resistance.

Figure 3
Figure 3 Senescence-based anti-tumor strategies.Inducing the senescence of tumor cells at early stages of tumor development is an effective anti-tumor concept.In late tumor stages, immunosuppression of the microenvironment and various treatment resistance elements are usually alleviated by elimination of senescent cells.Combined multi-disciplinary, multi-omics analyses using multiple technical methods are expected to reveal the intricate relationship between cellular senescence and tumor malignant transformation, and lead to more efficient tumor treatments in the future.