T-cell engager therapies, including bispecific T-cell engagers and the immune-mobilizing monoclonal T-cell receptor against cancer tebentafusp, are an emerging class of anticancer immunotherapy, with rapid expansion of the class since initial approval of blinatumomab in 2014 and with distinct dermatologic adverse events increasingly recognized across agents. Tebentafusp and talquetamab demonstrate highest rates of notable dermatologic toxicity reflecting on-target off-tumor cutaneous effects...Across agents, most dermatologic adverse events can be managed with topical corticosteroids, emollients, antihistamines, or brief courses of systemic corticosteroids without requiring treatment discontinuation. Recognition of these agent-specific and mechanistically linked patterns is essential for dermatologists as T-cell engager therapies become increasingly integrated into oncology practice.

Genomic loss of the HLA-haplotype carrying the HLA-A*02:01 restriction element was detected in a progressive metastasis, resulting in loss of presentation of tebentafusp's target antigen. Understanding mechanisms of resistance against synthetic cancer immunotherapies will be key to monitoring disease control and development of early intervention strategies towards cure.

Ongoing research explores tebentafusp in other settings, including cutaneous melanoma. Other ImmTACs, e.g. brenetefusp is being developed, underscoring the potential of this modality in cancer immunotherapy.

Local RT may enhance antigen release and T-cell recruitment, amplifying tebentafusp efficacy and inducing abscopal-like effects. Prospective studies are warranted to evaluate this combination and identify biomarkers predictive of response.

P2, N=19, Recruiting, Grupo Español Multidisciplinar de Melanoma

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. 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.

P2, N=378, Completed, Immunocore Ltd | Active, not recruiting --> Completed

Clinically, the bispecific T-cell redirection drug Tebentafusp has achieved a major breakthrough in metastatic uveal melanoma immunotherapy. This review systematically elucidates key driver gene mutations, chromosomal abnormalities, epigenetic alterations, and the unique immunosuppressive microenvironment of uveal melanoma, providing new insights into mechanisms of treatment resistance and guiding the development of innovative therapeutic strategies.

P2, N=44, Recruiting, Diwakar Davar | Trial completion date: Mar 2030 --> Sep 2030 | Trial primary completion date: Mar 2028 --> Sep 2028

UM is a rare but aggressive malignancy with limited treatment options once metastatic. Liver-directed strategies remain the mainstay of management, while novel systemic approaches, including tebentafusp, represent promising advances. Further research is required to improve survival and expand therapeutic opportunities.

This review synthesizes the current understanding of UM epidemiology, characteristics, prognostic biomarkers, immune biology, and contemporary management for both localized and metastatic disease. While survival gains remain modest, the rapid expansion of biologically informed and immune-based strategies offers cautious optimism for improving outcomes in this historically treatment-refractory disease.

Low HLA-A*02:01 positivity and limited access to tebentafusp remain major challenges in Türkiye. These findings provide an essential benchmark for improving treatment strategies in metastatic UM.