Antibody lectin chimeras targeting glycan shields to overcome tumor immune evasion

Tumor immune evasion remains one of the most persistent obstacles in cancer therapy. A key driver is aberrant glycosylation, a near-universal feature of malignant transformation that reshapes the tumor surface into a dense, immunosuppressive glycan shield. Hypersialylation, truncated O-glycans, and other tumor-associated carbohydrate antigens engage inhibitory receptors such as Siglec-7 and Siglec-9 on natural killer cells and macrophages, silencing innate immune surveillance. These glycan alterations also stabilize immune checkpoints, including PD-L1, and shield tumor antigens like HER2 and MUC1 from antibody recognition, limiting the effectiveness of conventional immunotherapies. Antibody-lectin chimeras (AbLecs) offer a structurally elegant solution. By fusing a tumor-targeting antibody, such as a HER2-directed IgG1, with a lectin-Fc decoy domain, AbLecs achieve dual recognition of protein antigens and hypersialylated glycan patterns simultaneously. This bivalently structured architecture increases avidity, physically excludes inhibitory Siglec receptors from the immunological synapse, and restores antibody-dependent cellular cytotoxicity and phagocytosis. Preclinical studies show that HER2-directed AbLecs outperform trastuzumab in reducing tumor burden and lung metastases in humanized Siglec mouse models, with limited off-tumor reactivity due to the weak baseline affinity of the lectin domain. This review covers tumor glycobiology, lectin biology, AbLec engineering, and antitumor mechanisms. Key challenges, including glycan heterogeneity, manufacturing complexity, and off-tumor toxicity, are discussed alongside glycomic biomarker strategies and combination regimens. AbLecs represent a meaningful advance in glyco-immunotherapy, turning the tumor glycocalyx from a protective shield into a viable therapeutic target.