Sialic acid containing glycans (sialoglycans) regulate tumor immunity by recruiting inhibitory Siglec receptors and suppressing leukocyte activation (Figure 1a). These glycans function alongside immune checkpoints such as PD1 and hypoxia-induced acidosis, collectively promoting immune evasion and therapeutic resistance (Figure 1a,b). Combination therapies simultaneously targeting these distinctly immunosuppressive axes thus represents a promising strategy to treat refractory cancers. This thesis explores two therapeutic strategies utilizing sialidase conjugates to specifically disrupt sialoglycan-mediated immunosuppression. First, I developed anti-PD1 antibody-sialidase conjugates (αPD1-S), selectively targeting PD1-expressing immune cells. Glycan profiling confirmed effective desialylation, while functional assays revealed enhanced T cell activation and cytotoxicity. In melanoma models, αPD1-S promoted inflammatory macrophage polarization, reduced T cell exhaustion, and restricted tumor growth compared to the current standard of care. Complementarily, I targeted sialoglycans on hypoxis tumors cells by engineering sialidase conjugates linked to carbonic anhydrase IX (CAIX) inhibitors (CAIXi-S). Structural and biochemical analyses validated CAIXi-S stability and dual functionality. These conjugates effectively reduced hypersialylation and enhanced antigen-specific T cell cytotoxicity. In triplenegative breast cancer models, CAIXi-S induced robust tumor regression, durable protective immunity, and favorable immune remodeling characterized by decreased T cell exhaustion and increased pro-inflammatory myeloid infiltration. Collectively, these findings underscore the therapeutic potential of sialoglycan removal from tumors and their resident immune cells.