Tumour-reactive T cells infiltrating solid tumours are often rendered exhausted, a cell differentiation state characterised by upregulation of inhibitory receptors and reduced effector function. The process of T-cell exhaustion permits cancer progression and interferes with immunotherapy response. Efforts to overcome T-cell exhaustion, such as immune checkpoint blockade (ICB), can lead to remarkable clinical responses in some patients with cancer. However, only a minority of patients respond to ICB, responses often lack durability, and undesirable immune-related toxicities are prevalent. Thus, elucidating additional factors that limit T-cell function in cancer may reveal new therapeutic targets to safely promote tumour eradication.

While persistent T-cell receptor (TCR) signalling due to chronic tumour antigen is a major driver of exhaustion, the suppressive tumour microenvironment (TME) also contributes.1 Over the last two decades, the ectoenzymes CD39 and CD73, which degrade extracellular ATP to adenosine, have been implicated in T-cell exhaustion.2 3 In cancer, stressed or damaged cells release ATP. Subsequently, CD39 and CD73 work in concert to convert extracellular ATP to adenosine, which has broad immunosuppressive effects.2 3 In T cells, adenosine regulates proximal TCR signalling events, thereby reducing T-cell effector function. CD39 is highly expressed on exhausted T cells found in human cancers4 5 and cancer or persistent viral infection mouse models.6–8

Here, Potenza et al 9 investigate the phenotypic traits of human T cells infiltrating colorectal cancer (CRC) tumours and metastases. Using transcriptional profiling, flow cytometry and …