Tebentafusp induces systemic immune activation, but tumor immune remodeling remains incompletely validated: a narrative review in metastatic uveal melanoma

Background Tebentafusp improves survival in HLA-A*02:01-positive metastatic uveal melanoma, yet the human evidence linking early systemic immune activation to remodeling of metastatic tumors is dispersed across overlapping translational reports. Methods We performed a PRISMA-style, search-informed narrative review and descriptive evidence mapping of human reports evaluating baseline or on-treatment immune measurements in tebentafusp-treated uveal melanoma. PubMed/MEDLINE, Embase, and CENTRAL were searched for reports published from January 2015 to 9 December 2025, with an updated search on 9 June 2026. Reports were linked to their underlying trial or cohort before synthesis. Results Overall, 286 records were screened, 21 full-text reports or complete abstracts were assessed, and 10 reports were retained. These represented three principal evidence units rather than 10 independent studies: NCT02570308, NCT03070392, and an independent serial skin-biopsy cohort. Blood-based analyses consistently showed early cytokine induction and transient lymphocyte changes after tebentafusp dosing. Paired metastatic-tissue analyses reported increased CD3 and CD8 cell density and interferon-response programs by day 16, but these observations derived predominantly from overlapping analyses of NCT02570308. Baseline and on-treatment immune features were associated with survival in exploratory analyses. Skin biopsies provided independent evidence of on-target cutaneous pharmacodynamics but only indirect evidence regarding metastatic tumor remodeling. Conclusion Tebentafusp is associated with consistently observed early systemic immune activation across overlapping analyses, but treatment-associated metastatic tumor immune remodeling remains incompletely validated. The available evidence supports temporal coherence rather than a proven causal systemic-to-tumor pathway. Future studies should use prospective paired blood and liver sampling, harmonized time points, prespecified immune endpoints, and mediation analyses linking immune changes to clinical outcomes.