The tumour microenvironment (TME) poses a significant obstacle to the success of chimeric antigen receptor (CAR) T cell immunotherapy in solid tumours. Here, the authors detail how both cellular and non-cellular components of the TME contribute to tumour resistance against CAR T cell therapy, and explore emerging strategies aimed at overcoming these barriers in order to enhance the efficacy of CAR T cell therapy.

In this Review, the authors discuss the latest advances in our understanding of organelle biology in T cell-mediated antitumour immunity and how this knowledge is being used to power the next generation of cancer immunotherapy applications through pharmacological or genetic manipulation of organelles and intercellular organelle transfer or organelle transplantation.

This Review explains how an improved understanding of immune and nervous system interactions in the central nervous system (CNS) has guided the use of immunotherapies (including chimeric antigen receptor T cells, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors) to treat CNS tumours. The authors highlight the outcomes of clinical trials that have used immunotherapy to treat primary brain cancers and provide a perspective on future directions for the field.

Here, Sun and Dong describe the many signals from stimulatory and inhibitory molecules as well as by microenvironmental factors, such as cytokines, metabolites and neuronal factors, that regulate CD8⁺ T cell exhaustion. They explain how these extrinsic factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through intrinsic cell regulators.