The Jekyll and Hyde Nature of Senescent Cancer Cells
The goal of the cancer research community is, broadly, to find ways to selectively stress, kill, and halt the replication of cancer cells. Researchers have been earnestly engaged in this work for decades. Cells that are stressed and damaged tend to become senescent, even cancer cells. Senescent cells cease to replicate and begin to secrete pro-inflammatory molecules to attract the attention of the immune system. Driving cancerous cells into senescence has long been recognized as a goal in cancer research, alongside the related goal of killing the cancerous cells outright. Any suitably cytotoxic therapy will typically achieve both of those outcomes at the same time. So it is perhaps not surprising to find that the first senolytic drugs capable of selectively destroying senescent cells outside the context of cancer are repurposed chemotherapeutics.
It is now recognized that destroying cancer leaves a patient with a lingering burden of senescent cells, and these additional senescent cells are likely the reason why cancer survivors exhibit a reduced life span and increased burden of age-related disease. There is little debate over the question of whether it is a good idea to use senolytics to clear these errant cells after the cancer is banished: if senolytics are good for patients in the context of a normal age-related accumulation of senescent cells, then they should be good for cancer survivors as well. The debate is instead to be found over the question of whether and when it is a good idea to destroy senescent cells during cancer treatment, while the cancer is still in evidence. Will it help or harm efforts to remove the cancer? The answer may vary on a cancer by cancer and therapy by therapy basis.
Beyond its connection to aging, senescence has been recognized as a hallmark of cancer. Whether senescence is beneficial or detrimental to cancer initiation, progression, and/or treatment has remained controversial over the past few decades. On one hand, the induction of senescence can serve as a barrier against malignant transformation and excessive hyperproliferation due to reduced proliferative capacity. On the other, SnC accumulation may act as a driver of cancer progression and therapy resistance, primarily mediated by inflammatory factors in the senescence-associated secretory phenotype (SASP). Persistent senescence has been associated with promoting malignant transformation, accelerating tumor growth, inducing cancer stemness, facilitating distant metastasis, maintaining chronic inflammation, and dampening the anti-tumor immune response.
Confirming these deleterious effects, genetic elimination of senescent cells (SnCs) was shown to delay spontaneous tumorigenesis and decrease cancer-related mortality. Senolytic agents, drugs that selectively eliminate SnCs, have also demonstrated significant potential in improving cancer therapies. Nonetheless, our studies have identified opposing, apparently beneficial, effects of therapy induced senescence (TIS), where SnCs may serve as a vaccine to drive an adaptive immune response to inhibit tumor growth and boost radiation therapy. This work is built on pioneering studies revealing innate and adaptive immune recognition of SnCs leading to their elimination and tumor suppression, often described as senescence surveillance.
Over the past decade, a growing literature has appeared that further defines roles for host immunity in mediating the anti-tumor effects of SnCs, as reflected in recent reviews. Multiple studies have implicated the upregulation of inflammatory mediators including damage-associated molecular patterns (DAMPs), chemotactic factors and other cytokines, and antigen presentation machinery in the activation of both innate and adaptive immune responses, not only driving SnC elimination via immune surveillance but also potentiating broader immune responses. Such findings highlight the positive aspects of TIS, extending beyond growth suppression to significantly enhance anti-tumor immunity.
A factor underlying the apparent inconsistency may be that SnCs, including those formed by cancer therapies, can express immune checkpoint ligands that allow SnCs to evade surveillance and protect their microenvironment. Thereby, some benefits of immune checkpoint blockade (ICB) therapy in combination with genotoxic or targeted therapies may be mediated by overcoming immunosuppression driven by TIS and restoring immune surveillance.
This review examines cellular senescence in the context of cancer, highlighting the diverse roles of SnCs in the tumor microenvironment (TME) and arguing for a broad view of senescence and its functions. We will discuss how the interaction between SnCs and the immune system can lead to either beneficial or detrimental outcomes depending on the specific features of SnCs, particularly the SASP. We will then review SASP modulation and SnC elimination via senolytics. Such approaches may limit the adverse effects of senescence while amplifying its beneficial impact, which ultimately presents an alternative strategy to improve cancer therapies.