Key barriers in utilizing advanced T-cell engager strategies on solid tumors.

INTRODUCTION: T cell engagers (TCEs) are engineered immune-mobilizing molecules that recruit T cells toward tumor cells. TCEs have demonstrated clinical efficacy in hematologic malignancies and currently show therapeutic potential in solid tumors through the approvals of tebentafusp and tarlatamab in uveal melanoma and small cell lung cancer. However, implementation of TCEs in solid tumors presents distinct challenges owing to tumor intrinsic features such as lack of specific antigens, biochemical and physical barriers that hinder T cell infiltration, complex immunosuppressive microenvironments, and intrinsic or acquired resistance to TCEs. AREAS COVERED: This review aims to cover inclusive overview of the current portrait of TCEs for the treatment of solid tumors. It provides the mechanisms and design principle of TCE and addresses the challenges that impede treatment efficacy. Especially, we extensively depict the primary and acquired resistance mechanisms to TCEs. Moreover, we highlight the next-generation directions such as engineering of antibody format and combination strategies to overcome these challenges and improve the clinical efficacy. EXPERT OPINION: Integrating logical target selection, advanced engineering, biomarker-guided patient stratification, and deliberate clinical design allows TCEs to successfully expand the reach of novel immunotherapeutics into solid tumors.