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Significance Targeting myeloid cells represents a promising strategy to augment antitumor immunity and overcome resistance to existing T cell-targeting therapies. However myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting Siglec-7 and Siglec-9 to enhance antitumor immunity in vivo. Using an immunocompetent mouse model humanized for Siglec-7/9, we show that these receptors inhibit the endogenous antitumor immune response in a tissue-specific manner. These Siglecs also restrict the response to tumor-targeting and checkpoint-targeting antibodies, highlighting their significance in combinatorial approaches to immunotherapy. Finally, we show that Siglec-7/9 blockade can significantly reduce tumor burden in vivo, supporting the use of antibodies targeting Siglec-7/9 to therapeutically enhance antitumor immunity.

Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity