Cancer Heterogeneity and Plasticity ISSN 2818-7792

Cancer Heterogeneity and Plasticity 2025;2(3):0013 | https://doi.org/10.47248/chp2502030013

Perspective Open Access

The Three Barriers Senescent Tumor Cells Must Overcome to Relapse

James G. Jackson

  • Department of Biochemistry and Molecular Biology, Tulane School of Medicine, 1430 Tulane Avenue, mail code 8643, New Orleans, LA 70112, USA

Academic Editor(s): Dean G. Tang

Received: May 28, 2025 | Accepted: Jul 27, 2025 | Published: Aug 4, 2025

Cite this article: Jackson JG. The Three Barriers Senescent Tumor Cells Must Overcome to Relapse. Cancer Heterog Plast. 2025;2(3):0013. https://doi.org/10.47248/chp2502030013

Abstract

Tumor cells that enter senescence as a response to treatment can be permanently arrested or removed by the immune system, resulting in favorable patient outcomes. Alternatively, many studies have now shown that, in some tumors, the senescent program enables tumor cell survival, persistence, and eventually relapse, resulting in poor patient outcomes. Whether senescence is a positive or negative factor is dependent on a clonal population of cells overcoming three critical barriers. First, senescence must enable survival from the initial stress of treatment, such as DNA damage, by preventing apoptosis and/or mitotic catastrophe. Senescent cells are also frequently immunogenic, thus, a second barrier is the activation of programs of immune evasion, such as PD-L1 expression, that outweigh the immunogenic properties. Third, senescent cells must escape their rigid arrest to proliferate again. Studies over the years have experimentally addressed challenging questions related to relapse and senescence, but more research is needed, particularly in vivo. Here, we discuss critical studies investigating how tumor cells that enter senescence as a response to treatment overcome barriers to relapse.

Keywords

Senescence, relapse, cell cycle arrest, immunotherapy, immune evasion, p53, PD-L1

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