CD24 signaling through macrophage Siglec-10 is a new target for cancer immunotherapy. Ovarian cancer and triple-negative breast cancer (TNBC) are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. This study shows that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a new, promising target for cancer immunotherapy. Cancer cells evade clearance by macrophages through overexpression of anti-phagocytic signals, including CD47, PD-L1, and B2M. Monoclonal antibodies that block these signals have shown therapeutic potential in several cancers, but variability in response suggests additional "don't eat me" signals. The study demonstrates a novel role for tumor-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor Siglec-10 on tumor-associated macrophages (TAMs). CD24 is highly expressed in many tumors, and TAMs express high levels of Siglec-10. Genetic ablation of CD24 or Siglec-10, and monoclonal antibody blockade of the CD24-Siglec-10 interaction, robustly enhance phagocytosis of CD24-expressing tumors. These findings highlight CD24 as a highly-expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential of CD24-blockade as cancer immunotherapy. CD24 is a potent anti-phagocytic signal that can directly protect cancer cells from attack by Siglec-10-expressing macrophages. Monoclonal antibody blockade of CD24-Siglec-10 signaling robustly enhances clearance of CD24+ tumors, indicating promise for CD24 blockade as immunotherapy. This study defines CD24-Siglec-10 as a novel innate immune checkpoint critical for mediating anti-tumor immunity and provides evidence for the therapeutic potential of CD24 blockade, with particular promise for the treatment of ovarian cancer and breast cancer.CD24 signaling through macrophage Siglec-10 is a new target for cancer immunotherapy. Ovarian cancer and triple-negative breast cancer (TNBC) are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. This study shows that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a new, promising target for cancer immunotherapy. Cancer cells evade clearance by macrophages through overexpression of anti-phagocytic signals, including CD47, PD-L1, and B2M. Monoclonal antibodies that block these signals have shown therapeutic potential in several cancers, but variability in response suggests additional "don't eat me" signals. The study demonstrates a novel role for tumor-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor Siglec-10 on tumor-associated macrophages (TAMs). CD24 is highly expressed in many tumors, and TAMs express high levels of Siglec-10. Genetic ablation of CD24 or Siglec-10, and monoclonal antibody blockade of the CD24-Siglec-10 interaction, robustly enhance phagocytosis of CD24-expressing tumors. These findings highlight CD24 as a highly-expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential of CD24-blockade as cancer immunotherapy. CD24 is a potent anti-phagocytic signal that can directly protect cancer cells from attack by Siglec-10-expressing macrophages. Monoclonal antibody blockade of CD24-Siglec-10 signaling robustly enhances clearance of CD24+ tumors, indicating promise for CD24 blockade as immunotherapy. This study defines CD24-Siglec-10 as a novel innate immune checkpoint critical for mediating anti-tumor immunity and provides evidence for the therapeutic potential of CD24 blockade, with particular promise for the treatment of ovarian cancer and breast cancer.