The diversity of CD8⁺ T cell dysfunction in cancer and viral infection

CD8⁺ T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection. Here, we discuss the molecular and spatiotemporal mechanisms beyond exhaustion that underlie the inability of CD8⁺ T cells to eradicate malignant or chronically infected cells. We also propose a framework to enhance our understanding of these mechanisms - which include tolerization, anergy, senescence, cell death, exclusion and ignorance - with the ultimate aim of informing novel approaches to improve the clinical management of cancer and chronic viral infection.