The impact of Foxp3⁺ regulatory T-cells on CD8⁺ T-cell dysfunction in tumour microenvironments and responses to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy, inducing durable remissions in responding patients. However, they are associated with variable outcomes, spanning from disease hyperprogression to complete responses with the onset of immune-related adverse events. The consequences of checkpoint inhibition on Foxp3(+) regulatory T (T-reg) cells remain unclear but could provide key insights into these variable outcomes. In this review, we first cover the mechanisms that underlie the development of hot and cold tumour microenvironments, which determine the efficacy of immunotherapy. We then outline how differences in tumour-intrinsic immunogenicity, T-cell trafficking, local metabolic environments and inhibitory checkpoint signalling differentially impair CD8(+) T-cell function in tumour microenvironments, all the while promoting T-reg-cell suppressive activity. Finally, we focus on the mechanisms that enable the induction of polyfunctional CD8(+) T-cells upon checkpoint blockade and discuss the role of ICI-induced T-reg-cell reactivation in acquired resistance to treatment.