In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.

Over the last decades, new therapies have greatly improved the treatment of different cancer types. For example, immunotherapy is the collective of therapies that aims to recruit and stimulate the patient's own immune system to eradicate the tumor. 1 The tumor microenvironment (TME) comprises a great variety of cells, including endothelial cells, fibroblasts, and immune cells. Immune cells in the TME play a crucial role during cancer progression. Via immunosurveillance, immune cells are able to identify and eliminate malignant cells in the early stages. 2 However, certain mutations may cause adaptations that allow tumor cells to go undetected, for example, by downregulating MHC molecules. In addition, tumor cells may upregulate immunosuppressive molecules or secrete immunosuppressive cytokines to resist immune-mediated destruction. [3][4][5] Recruitment of immunosuppressive cells to the TME further polarizes the TME to an anti-inflammatory environment that prevents tumor killing and promotes disease progression. 6,7 Various types of agents to promote the immune system to eliminate tumor cells are in development or have become the standard of care in the treatment of cancer patients. This includes monoclonal antibodies (mAbs), adoptive (CAR) T cell transfer, or dendritic cell (DC) vaccination. Monoclonal antibodies include checkpoint inhibitors as well as tumor-associated antigen (TAA)-targeting antibodies directed against membrane components