Blockade

Biology

Immune checkpoint

T cell

Receptor

Cancer research

Computational biology

Immunology

Cancer immunotherapy

Immune system

Tumor microenvironment

Internal medicine

Medicine

Immunotherapy

Nature Reviews Drug Discovery

The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell–cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects — beyond T cell co-receptors — of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types. Although checkpoint inhibitor blockade has been extremely successful in certain types of cancer, harnessing the immune system for immunosurveillance has met with numerous failures. In this Review, Mak and colleagues discuss the lessons learned from these failures, and how to incorporate the growing understanding of immuno-oncology into potential therapies, including combinations with existing checkpoint inhibitors.

Beyond immune checkpoint blockade: emerging immunological strategies