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For decades, cancer was considered a disease driven by genetic mutations in tumor cells, therefore afflicting a single cell type. This simplified view was slowly replaced by the understanding that interactions between malignant cells and neighboring stromal and immune cells—the tumor microenvironment (TME)—profoundly shape cancer progression. This understanding paved the way for an entirely new form of therapy that targets the immune cell compartment, which has revolutionized the treatment of cancer. In particular, agents activating T lymphocytes have become a key focus of these therapies, as they can induce durable responses in several cancer types. However, T cell targeting agents only benefit a fraction of patients. Thus, it is crucial to identify the roles of other immune cell types in the TME and understand how they influence T cell function and/or whether they present valuable therapeutic targets themselves. In this review, we focus on the myeloid compartment of the TME, a heterogeneous mix of cell types with diverse effector functions. We describe how distinct myeloid cell types can act as enemies of cancer cells by inducing or enhancing an existing immune response, while others act as strong allies, supporting tumor cells in their malignant growth and establishing an immune evasive TME. Specifically, we focus on the role of myeloid cells in the response and resistance to immunotherapy, and how modulating their numbers and/or state could provide alternative therapeutic entry-points.

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