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Fc receptors (FcRs) and the microbiome are both known to have an effect on the development and progression of cancers. Checkpoint inhibitors are a novel class of therapeutics which are used to combat cancer and are integrally linked to both FcRs and the microbiome. The use of checkpoint inhibitors has grown exponentially over the past decade, although many host factors affect both the efficacy and the safety of these therapeutics. Some of these host factors, including the microbiome and the expression of FcRs, are currently being investigated. Here we discuss the current understanding of FcRs (particularly the inhibitory FcγRIIB) and the microbiome in context of T cell immunity, inflammation, cancer, and checkpoint inhibition., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)