Güç, EsraTreveil, AgathaLeach, EmmaBroomfield, AnnaCamera, AntonioClubley, JamesNieto García, PaulaKazachenka, AnastasiyaKhanolkar, RahulCarpio, Luis P. delHeyn, HolgerHassel, Jessica C.Sacco, Joseph J.Stanhope, SarahCollins, LauraPiulats, Josep M.Ranade, KoustubhBenlahrech, Adel2025-07-082025-07-082025-03-102041-1723https://hdl.handle.net/2445/222076Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01+ adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR = 2.09, 95% CI, 1.31-3.33, p = 0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM.16 p.application/pdfengcc-by-nc-nd (c) Güç et al., 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/TerapèuticaCàncerTherapeuticsCancerinfo:eu-repo/semantics/article2025-06-06info:eu-repo/semantics/openAccess40064880