Cellular senescence and SASP in tumor progression and therapeutic opportunities

Abstract

Cellular senescence (CS), a permanent and irreversible arrest of the cell cycle and proliferation leading to the degeneration of cellular structure and function, has been implicated in various key physiological and pathological processes, particularly in cancer. Initially, CS was recognized as a barrier to tumorigenesis, serving as an intrinsic defense mechanism to protect cells from malignant transformation. However, increasing evidence suggests that senescent cells can promote tumor progression to overt malignancy, primarily through a set of factors known as senescence-associated secretory phenotypes (SASPs), including chemokines, growth factors, cytokines, and stromal metalloproteinases. These factors significantly reshape the tumor microenvironment (TME), enabling tumors to evade immune destruction. Interestingly, some studies have also suggested that SASPs may impede tumor development by enhancing immunosurveillance. These opposing roles highlight the complexity and heterogeneity of CS and SASPs in diverse cancers. Consequently, there has been growing interest in pharmacological interventions targeting CS or SASPs in cancer therapy, such as senolytics and senomorphics, to either promote the clearance of senescent cells or mitigate the harmful effects of SASPs. In this review, we will interpret the concept of CS, delve into the role of SASPs in reshaping the TME, and summarize recent advances in anti-tumor strategies targeting CS or SASPs.

Keywords: Cellular senescence; SASP; Therapy; Tumor; Tumor microenvironment.

Fig. 1

Factors inducing cellular senescence (CS). CS can be triggered by various factors, including oncogenes, telomere shortening, mitochondrial dysfunction, DNA damage response (DDR), protein homeostasis disorders, and chemoradiotherapy

Fig. 2

Signaling pathways involved in CS. During DNA replication, telomeres progressively shorten, triggering a DDR and DSB, which activate ATM and ATR, leading to the activation of CHK2. This activation blocks E2F transcription through the p53/p21 and p16/RB pathways, causing the cell cycle to arrest in the G1 phase. Additionally, OIS and TIS can also initiate DDR and DSB, ultimately leading to cell cycle arrest

Fig. 3

The double-edged sword effect of SASP in tumors. The SASP exhibits dual roles in tumor dynamics. On one side, it enforces cell cycle arrest, thereby inhibiting tumor cell proliferation. Additionally, SASP recruits immune cells to clear senescent cells, bolstering immunosurveillance and enhancing antigen presentation. On the opposite side, SASP can promote tumor cell proliferation, facilitate the emergence of cancer stem cells and EMT, and suppress immune responses, contributing to tumor progression and immune evasion

Fig. 4

Mechanism of senolytics and senomorphics. Senolytics induce apoptosis in cells undergoing CS by targeting various SCAPs. These pathways include MDM2, Bcl-2 family members, HSP90, SA-β-gal, PI3K/AKT, Na⁺-K⁺ pumps, FOXO4, and ADC. On the other hand, senomorphics inhibit pathways like NF-κB, MAPK, mTOR, and Bcl-2, thereby preventing senescent cells from releasing SASP factors such as IL-6, IL-8, MMP, and others