Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment

SIMPLE SUMMARY: Immunotherapies have changed the way we treat cancer and, while some patients have benefitted greatly, there are still those that do not respond to therapy. Understanding why some patients respond to therapy and others do not is critical in developing new immunotherapeutic strategies. The increasing awareness of the importance of investigating the tumour in its entirety, including the surrounding tissue and role of various immune cells is helping to differentiate responders and non-responders. In addition, the resolution gained by the development of sophisticated bioinformatic technologies allows for a deeper understanding of the complex roles of individual cells in the tumour. This advancement will be critical for the development of novel therapies to treat cancer. ABSTRACT: Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies.