Next-generation T cell engagers in oncology: Pharmacologic evolution from bispecific to trispecific antibodies

Recent advances in immuno-oncology have led to the development of innovative T cell-engaging therapies, transforming the treatment landscape for hematologic and solid malignancies. Bispecific T cell engagers (BiTEs) have demonstrated clinical efficacy by redirecting T cell cytotoxicity toward tumor cells, yet challenges such as antigen escape, safety concerns, and limited durability remain. Building on the foundation established by BiTEs, the emergence of trispecific T cell engagers promises enhanced tumor selectivity, improved pharmacodynamic profiles, and potentially superior clinical outcomes. This minireview summarizes the pharmacology of T cell engagers, with a focus on the mechanistic evolution from BiTEs to next-generation trispecific antibodies. We highlight recent advances in molecular design, summarize current clinical evidence, and address ongoing challenges in drug development and safety. By critically synthesizing the latest preclinical and clinical findings, this review aims to inform future research directions and optimize the clinical translation of next-generation T cell-engaging therapeutics. SIGNIFICANCE STATEMENT: This minireview synthesizes current knowledge on the pharmacology of T cell engagers, spotlighting the shift from bispecifics to trispecifics, and provides insights essential for advancing safer and more effective immunotherapies in oncology.