Fcγ receptors—Master regulators of antibody therapy

Antibody therapeutics have been at the heart of transformative cancer treatment for more than 20 years: first with antibodies directly targeting the tumor and more recently with immune checkpoint blockade. Despite their impact and widespread utilization, antibody therapy mechanisms of action and factors governing response or resistance in patients are still poorly understood. One aspect that has emerged as important for all clinically developed antibodies is antibody Fc interactions with Fcγ receptors. Antibody Fc acts to connect the specificity of antibody to the power of the innate immune system and ensuing adaptive immunity. What has become clear is that in the context of both direct tumor-targeting and ICB mAbs, these interactions can be pivotal to therapeutic activity and survival. Through improved understanding and evolving strategies of Fc engineering, FcγR blockade, and pharmacological modulation of immune effector cell FcγR expression, we are at the dawn of harnessing the power of already clinically validated and new classes of antibody-based cancer immunotherapeutics. Current understanding including the impact and consequence of Fc:Fcγ receptor interactions in defining antibody efficacy and resistance is discussed here for developed antibody classes together with strategies to enhance these to increase patient responses and overcome resistance.