Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.

CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype associate with favourable prognoses, the tumour microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features. Here, we deconvolute TRM and TEX cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. While TRM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Tumour-associated TEX and TRM cells are clonally distinct, with the latter comprising tumour-independent bystanders and tumour-specific cells segregated from cognate antigen. Intratumoural TRM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumour-associated TEX and TRM populations. These results suggest unique roles for TRM and TEX cells in tumour control, underscoring the need for distinct strategies to harness these populations in novel cancer therapies.