Use of immune checkpoint inhibitors targeting the programmed cell death protein-1/programmed cell death-ligand 1 and cytotoxic T lymphocyte-associated protein-4 axes has yielded impressive results in some clinical trials. However, only a subset of patients initially respond to these inhibitors, and increasing clinical evidence indicates that a substantial proportion of initial responders ultimately relapse with lethal, drug-resistant disease months or years later. Studies that have used massively parallel sequencing have shed light on the rich functional landscape of mutations that endow tumour cells with the ability to evade T-cell-mediated immunosurveillance. Cancer genomes bear signatures of clonal evolution and selection, particularly implicating acquired defects in interferon receptor signalling and antigen presentation. In this Review, we discuss the biological processes that operate in the formation of so-called immunoresistant niches, and describe the latest progress in the development of combination strategies to reinstate immunosurveillance in immune-refractory tumours.