Stanczak et al. showed that hypersialylation on tumor cells promotes polarization of TAMs towards an immunosuppressive phenotype through interactions with Siglec-E, contributing to disease progression and immune escape. Genetic and therapeutic targeting of the sialoglycan-Siglec axis, either through desialylation or targeted removal of Siglec-E, promoted the repolarization of TAMs and supported stronger antitumor immune responses, particularly in the setting of immune checkpoint blockade. These results support further investigation of therapeutic desialylation as a potential immunotherapy.