T cell dysfunction and therapeutic intervention in cancer

Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer. In this Review, the authors analyze functional and dysfunctional T cell features to make sense of cancer immunotherapy efficacy and how to improve it.