Peptide hydrogel boosts the cytotoxic and metabolic fitness of Vγ9Vδ2 T cells in melanoma immunotherapy

Background Adoptive cell therapy with Vγ9Vδ2 T cells represents a promising approach for melanoma treatment. However, its efficacy is often limited by poor persistence, inadequate tumor infiltration, and functional suppression within the tumor microenvironment. Peptide-based hydrogel as a vehicle has exhibited great potential for delivery of biologics and enhancement of their function, but their ability to directly modulate the metabolic and cytotoxic fitness of Vγ9Vδ2 T cells remains largely unexplored. Methods We developed a peptide hydrogel (Self-assembly material based on peptide Nap-GFFF, named as SAM.1) and assessed its ability to activate Vγ9Vδ2 T-cell and amplify their cytotoxicity to A375 melanoma cells in vitro , and to enhance antitumor efficacy in a melanoma xenograft model. Mechanistic studies focused on integrin signaling, PI3K/AKT/mTOR activation, and metabolic reprogramming. Results SAM.1 significantly enhanced the cytotoxic activity of Vγ9Vδ2 T cells against A375 melanoma cells in vitro . It promoted Vγ9Vδ2-T cell activation, evidenced by increased CD25 and CD69 expression, and boosted the secretion of key cytotoxic effector molecules such as IFN-γ, TNF-α and perforin. Mechanistically, SAM.1 engaged integrin signaling (upregulating CD11c and CD103), leading to activation of the PI3K/AKT/mTOR pathway. This signaling cascade drove a beneficial metabolic reprogramming, shifting T cell energy production from glycolysis towards oxidative phosphorylation, thereby enhancing their bioenergetic capacity. Beyond that, peritumoral delivery of Vγ9Vδ2 T cells increased intratumoral T cell infiltration. As a result, melanoma growth was inhibited after administration of SAM.1 encapsulating Vγ9Vδ2 T cells. Conclusion SAM.1 hydrogel acted as a two-in-one scaffold, controlled release and an immunomodulatory agent, to enhance the persistence and antitumor function of Vγ9Vδ2 T cells. This strategy provided a new paradigm for γδ T-cell–based immunotherapy in melanoma.