Decoding T cell senescence in cancer: Is revisiting required?

Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term “senescence” has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of “truly” senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.