Targeting Senescence in Oncology: An Emerging Therapeutic Avenue for Cancer

Abstract

Since cancer is often linked to the aging process, the importance of cellular senescence in cancer has come under the spotlight. While senescence in cancer cells can serve as a natural barrier against cancer due to its proliferation arrest, its secretory phenotypes and alterations in the surface proteome can paradoxically promote or suppress tumor progression. Senescent cancer-associated fibroblasts, endothelial cells, and immune cells can also contribute to cancer promotion. During therapeutic interventions for cancer, not only their therapeutic effects, but also therapy-induced senescence may have an impact on cancer outcomes. Senotherapeutics, therapy targeting senescent cells, have been reported as novel cancer therapy in recent studies, and the combination of senescence induction and senotherapeutics has been increasingly recognized. Although some clinical trials of senotherapeutic drugs for cancer with or without senescence-inducible therapy are ongoing, there is as yet no satisfactory clinical application. With further research into targeting senescence in oncology, it is expected that senotherapeutics, particularly in combination with senescence-inducing therapy, will become a novel therapeutic strategy.

Keywords: cancer; cellular senescence; senotherapeutics; therapy-induced senescence; tumor microenvironment.

Figure 1

Senescence promotes or suppresses cancer. In a tumor microenvironment, cellular senescence can occur in cancer cells, stroma, and immune cells via physiological or pathological stress. While senescence in cancer cells commonly exhibits tumor-suppressive effects via cell cycle arrest, the recruitment of immune cells, and surface proteome alteration, senescence can paradoxically contribute to tumor growth through several mechanisms that create an immune-suppressive and cancer-favorable microenvironment. The figures were created by Adobe Illustrator and Photoshop. CAFs, cancer-associated fibroblasts; SASP, senescence-associated secretory phenotype; NK cells, natural killer cells; MDSCs, myeloid-derived suppressor cells; T reg cells, regulatory T cells; PD-L1/2, programmed death ligand 1/2; ICAM1, intercellular adhesion molecule 1; EGFR, epidermal growth factor receptor; IFNGR1, interferon gamma receptor 1; MHC-class1, major histocompatibility complex class 1; MICA, MHC class I polypeptide-related sequence A; ULBP2, UL16 binding protein 2; HLA-E, human leukocyte antigen-E.

Figure 2

“One-two punch” strategy upon therapy-induced senescence.