Disrupting the balance between activating and inhibitory receptors of γδT cells for effective cancer immunotherapy

Abstract

γδT cell biology in cancer has been studied for decades but remains poorly understood mainly due to species differences in preclinical models and a lack of appropriate analytical tools. This lack of knowledge has hindered the clinical translation of promising therapeutic concepts. In recent years, advanced single-cell analysis techniques and comprehensive protein–protein interaction studies have transformed our understanding of γδT cells and their receptors. This insight has revealed new opportunities and challenges in harnessing γδT cells for therapeutic purposes. In this context, we will discuss the latest findings in γδT cell biology, with a special focus on their role in cancer immune therapies. We will explore strategies to overcome tolerance and shift the balance of γδT cells and their receptors towards antitumour efficacy, which has the potential to successfully translate into various engineering approaches in cancer immunotherapy. In this Review, Beringer and colleagues highlight how future strategies for developing immunotherapies using γδT cells and their receptors will depend on creating intentional imbalances between activating and inhibitory receptors through the genetic engineering of γδT cell-inspired biologics and cellular therapies.