Abstract T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell–mediated cytotoxicity. While TCEs have demonstrated remarkable efficacy in hematologic malignancies, translation into solid tumors has been more challenging. Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and PRAME among others. Unique challenges in solid tumors include antigen heterogeneity and density thresholds, on-target/off-tumor toxicities, and physical and immunologic barriers within the tumor microenvironment. To address these, next-generation engineering strategies, such as half-life extension, protease- or context-dependent masking, multispecificity, and “armed” constructs incorporating cytokine or co-stimulatory payloads, are being developed to enhance intratumoral activity while limiting systemic toxicities. Combination regimens with checkpoint blockade, chemotherapy, targeted therapies, and oncolytic platforms are also being actively investigated to overcome immune resistance and improve durability of response. Collectively, next-generation TCEs guided by rational target selection, context-dependent activation, and biomarker-driven patient stratification, are poised to broaden the reach of immunotherapy in solid tumors. In this review, we synthesize the recent advances that aim to expand the therapeutic window of TCEs for the treatment of solid tumors.
Garcia-Lorenzo et al. (2026) studied this question.