Trispecific antibodies in cancer therapy: Mechanisms, clinical progress and future directions

Trispecific antibodies represent an emerging class of next-generation antibody therapeutics, with growing relevance in cancer immunotherapy. By simultaneously engaging three distinct targets, these molecules are designed to integrate multiple antitumor mechanisms, thereby augmenting immune-mediated tumor cell elimination. Despite this conceptual appeal, the development and clinical translation of trispecific antibodies remain at an early stage. This review summarizes the current clinical landscape of trispecific antibody candidates and discusses the molecular and mechanistic principles underpinning recent advances in their design. Early clinical experience in hematological malignancies and selected solid tumors indicates encouraging antitumor activity with generally manageable safety profiles. However, the intrinsic structural complexity of trispecific antibody formats poses substantial challenges for large-scale manufacturing, contributing to increased production costs. In addition, pharmacokinetic limitations-including in vivo stability, systemic half-life, and tissue penetration-remain to be fully optimized. Immunogenicity-related toxicities, together with the long-term balance between efficacy and safety, also represent critical issues that necessitate careful clinical evaluation. Overall, trispecific antibodies hold considerable promise for expanding the therapeutic scope of cancer immunotherapy. Continued advances in molecular engineering, bioprocess development, and clinical investigation will be essential to overcome existing barriers and to realize their full therapeutic potential.