T-cell engagers in solid tumors: challenges and emerging strategies
Abstract
T-cell engagers (TCEs) redirect endogenous T cells toward malignant cells by simultaneously binding a tumor-associated target and a T-cell receptor component, most commonly CD3, thereby inducing immune-synapse formation and cytotoxicity independently of conventional antigen recognition. Although TCEs have transformed the treatment of several hematologic malignancies, their development in solid tumors remain limited by heterogeneous and non–tumor-specific antigen expression, impaired tumor penetration and T-cell trafficking, an immunosuppressive tumor microenvironment, and immune-mediated toxicities. This review examines the structural and mechanistic foundations of TCE activity, including antibody fragment–based constructs, IgG-like bispecific antibodies, T-cell receptor–based engagers, and emerging multispecific platforms. We discuss how molecular size, valency, geometry, epitope location, binding affinity, and pharmacokinetic engineering influence immune-synapse quality, antitumor potency, cytokine release, tissue distribution. Major barrier efficacy, including on-target, off-tumor toxicity, antigen heterogeneity and escape, restricted T-cell infiltration, T-cell exhaustion, and metabolic and immunologic suppression are critically evaluated. The evolving clinical landscape across major solid tumors is reviewed, with emphasis on tebentafusp in metastatic uveal melanoma and tarlatamab in previously treated small-cell lung cancer, illustrating the importance of aligning target biology, molecular format, and dosing strategy. We also address cytokine release syndrome, neurologic toxicity, resistance, and treatment failure and highlight strategies designed to widen the therapeutic window and sustain antitumor activity, including step-up dosing, affinity and avidity tuning, conditional or protease-activated constructs, dual-target and trispecific platforms, localized or genetically encoded delivery, rational combinations, and predictive biomarkers. Together, these advances are positioning TCEs as an increasingly adaptable and durable therapeutic platform for solid tumors.
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BibTeX
@article{forero2026tcell,
title = {{T-cell engagers in solid tumors: challenges and emerging strategies}},
author = {Jose Forero and Ruchi Jani and Xena Zheng and Chinmay Jani and Marijo Bilusic},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1956728},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1956728},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - T-cell engagers in solid tumors: challenges and emerging strategies
AU - Jose Forero
AU - Ruchi Jani
AU - Xena Zheng
AU - Chinmay Jani
AU - Marijo Bilusic
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1956728
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1956728
AB - T-cell engagers (TCEs) redirect endogenous T cells toward malignant cells by simultaneously binding a tumor-associated target and a T-cell receptor component, most commonly CD3, thereby inducing immune-synapse formation and cytotoxicity independently of conventional antigen recognition. Although TCEs have transformed the treatment of several hematologic malignancies, their development in solid tumors remain limited by heterogeneous and non–tumor-specific antigen expression, impaired tumor penetration and T-cell trafficking, an immunosuppressive tumor microenvironment, and immune-mediated toxicities. This review examines the structural and mechanistic foundations of TCE activity, including antibody fragment–based constructs, IgG-like bispecific antibodies, T-cell receptor–based engagers, and emerging multispecific platforms. We discuss how molecular size, valency, geometry, epitope location, binding affinity, and pharmacokinetic engineering influence immune-synapse quality, antitumor potency, cytokine release, tissue distribution. Major barrier efficacy, including on-target, off-tumor toxicity, antigen heterogeneity and escape, restricted T-cell infiltration, T-cell exhaustion, and metabolic and immunologic suppression are critically evaluated. The evolving clinical landscape across major solid tumors is reviewed, with emphasis on tebentafusp in metastatic uveal melanoma and tarlatamab in previously treated small-cell lung cancer, illustrating the importance of aligning target biology, molecular format, and dosing strategy. We also address cytokine release syndrome, neurologic toxicity, resistance, and treatment failure and highlight strategies designed to widen the therapeutic window and sustain antitumor activity, including step-up dosing, affinity and avidity tuning, conditional or protease-activated constructs, dual-target and trispecific platforms, localized or genetically encoded delivery, rational combinations, and predictive biomarkers. Together, these advances are positioning TCEs as an increasingly adaptable and durable therapeutic platform for solid tumors.
SN - 1664-3224
ER -