Fig. 1

Outlining CD8⁺ T cell evolution in cancer. (A) On the way to terminally differentiated states, naïve CD8⁺ T cells in cancer move through a meshwork of transcriptomically distinct phenotypes. The cells may stroll down the exhausted (top) or memory (bottom) thoroughfare, though memory cells can give rise to exhausted cells after acquiring the epigenetic imprints and the T_RM branch has clear transcriptional idiosyncrasies. In general terms, progression through either lane sees the waning of stem-like features and reprogrammability by immunotherapy and eventual fate convergence at the T_TEX terminus. T_EX^EFF and T_EMRA are lineage-wise juxtaposed with T_PEX but infused with heightened effector capacities. (B) Subsets of T_EX are identifiable by the expression of an assortment of TFs and surface proteins. T_PEX are vital to maintaining the exhausted T cell populations due to their stem-like features and capabilities to self-renew, as indicated by TCF1 expression, whereas TOX marks the inability of exhausted cells to fully reconstitute the memory or effector functions. The quiescent T_PEX1 subset is distinguished from the mobilised ones by SLAMF6 and CD69 expression profiles. The activated state of T_PEX2 is illustrated by the acquisition of the proliferative marker MKI67 and effector molecules IFN-γ and TNF-α, whose expression plateaus in T_INT before returning to low levels in T_TEX. In addition to escalation of immune checkpoint molecules (e.g., PD-1), T_TEX also express terminal exhaustion makers (e.g., CD39 and TIM-3). T_EX^EFF may form in place of T_TEX only under certain circumstances such as T_H-derived IL-21 induction. T_EX differentiation is under the oversight of an extensive, tightly regulated TF network, as shown in the figure. Notably, many of the TFs maintaining the T_PEX population are implicated in memory formation, and those propelling their differentiation support the effector cells during acute infection.