Bispecific Antibodies in Solid Tumors: Mechanistic Insights, Clinical Advances, and Future Directions

A rapidly advancing class of engineered immunoglobulins, known as bispecific antibodies (bsAbs), that bind two distinct antigens offers new approaches for tumor targeting and immune modulation. BsAbs function as immune cell engagers, immune checkpoint modulators, or signaling pathway inhibitors. They differ in half-life, stability, and tissue penetration depending on whether they exist in crystallizable fragment (Fc)-based or fragment-based formats. Although bsAbs have shown strong efficacy in hematologic malignancies, their translation to solid tumors has been limited by antigen heterogeneity, off-tumor toxicity, and the immunosuppressive tumor microenvironment. Recent clinical advancements have led to eight approved bsAbs for solid tumors, including amivantamab for EGFR (epidermal growth factor receptor) exon 20 insertion-mutated non-small cell lung cancer (NSCLC), tebentafusp for uveal melanoma, cadonilimab for cervical cancer, tarlatamab for small cell lung cancer, ivonescimab for PD-L1 (programmed death-ligand 1)-positive NSCLC, zanidatamab for HER2 (human epidermal growth factor receptor 2)-amplified biliary tract cancer, zenocutuzumab for NRG1 (neuregulin 1) fusion-positive tumors, and catumaxomab for malignant ascites. These agents have demonstrated durable clinical benefit with manageable safety profiles. However, class-related toxicities such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and on-target off-tumor effects remain important challenges. Advances in Fc silencing, affinity tuning, and tumor-restricted activation have improved therapeutic selectivity and tolerability. Ongoing innovations include bsAb-drug conjugates, proteolysis-targeting chimeras (PROTACs), and multispecific antibody platforms designed to reprogram the tumor microenvironment and enhance immune infiltration. Biomarker-driven patient selection and rational combination strategies are expected to further improve outcomes. As engineering technologies mature, bsAbs are expected to become integral to precision oncology, expanding safe and effective immunotherapy options for patients with solid tumors. This review aims to provide a comprehensive overview of the mechanisms, clinical applications, challenges, and future directions of bsAbs in solid tumors.