While immune checkpoint inhibitors have transformed treatment for many cancers, their benefit remains limited across all tumor types and is constrained by immune-related toxicity. Targeted immunotherapies, including T-cell engagers (TCEs), offer a more selective strategy by directing immune activity toward tumor-associated antigens. TCEs have achieved major success in hematologic malignancies and now show promise in selected solid tumors, with the approvals of tebentafusp and tarlatamab in uveal melanoma and small cell lung cancer, respectively, establishing proof of concept that durable benefit is possible. However, TCE efficacy is balanced by class-specific toxicities such as cytokine release syndrome and neurotoxicity, as well as on-target off-tumor effects. Antibody-drug conjugates (ADCs) can also enhance the specificity of cancer treatment by directing cytotoxic activity toward tumor cells via specific targets. ADC-checkpoint inhibitor combinations are similarly reshaping solid tumor therapy, most notably in urothelial carcinoma, where enfortumab vedotin plus pembrolizumab has demonstrated substantial survival gains. Across both strategies, efficacy may be influenced by antigen density, tumor heterogeneity, microenvironmental suppression, and treatment sequencing. Emerging drug engineering approaches and biomarker-driven patient selection aim to improve efficacy while limiting toxicity. Together, these advances support a new era of precision immuno-oncology, but broader success will require improved biomarkers, rational combinations, and an understanding of resistance mechanisms.
Ahn et al. (Thu,) studied this question.