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In T cell biology, ‘exhaustion’ was initially described as a hyporesponsive state in CD8 + T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term ‘exhaustion’ is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The upregulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8 + T cells, CD4 + T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Upregulation of the same inhibitory receptors that are associated with CD8 + T-cell exhaustion has also been identified in CD4 + T cells in chronic infections and cancers, suggesting a similar CD4 + T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4 + T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust antitumor immune response.

A variety of ‘exhausted’ T cells in the tumor microenvironment