Immune checkpoint blockade has revolutionized opportunities for therapeutic intervention in cancer but demonstrates a low frequency of response in most patients and in some common types of tumors. An emerging paradigm supports the notion that trillions of normally beneficial microbes inhabiting the gastrointestinal tract, termed the microbiota, critically impact the success or failure of antitumor immunity induced by immune checkpoint blockade. Here, we briefly summarize the current knowledge on how interactions between the microbiota and immune system are contributing to the outcome of cancer immunotherapy. We propose that this immune–microbiota dialogue is particularly important in gastrointestinal cancers that exhibit striking resistance to immune checkpoint blockade and inherently develop in a unique environment that is rich in both immune-cell networks and direct exposure to the microbiota. Finally, we focus on how future studies should determine whether microbiota can be harnessed as a strategy to boost antitumor immunity in these contexts and beyond.

See related article, p. 1291

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