Abstract
Adoptive Cell Therapy (ACT) has achieved curative responses in hematological malignancies, yet its translation to solid tumors remains limited by manufacturing bottlenecks, systemic toxicities, and poor T-cell infiltration and persistence within the immunosuppressive tumor microenvironment (TME). Here, we report the development and mechanism of ACTIVATE (Adoptive Cell Therapy and Immunostimulatory Vehicle for Anti-Tumor Efficacy), which leverages an injectable hydrogel depot technology that forms a transient inflammatory niche for localized co-delivery of adoptive T cells and native cytokines. By tuning cytokine identity, ACTIVATE enables precise modulation of T-cell expansion, effector function, and interaction with endogenous immune networks. We found that enhancing T-cell proliferation alone is insufficient to drive robust tumor control; instead, coordinated engagement of both adoptive and endogenous immune responses is critical for durable anti-tumor efficacy. In vivo , this orchestration via ACTIVATE led to enhanced infiltration and cytotoxicity of both adoptive and host-derived immune effectors, while driving robust recruitment and activation of T cells, B cells, dendritic cells, and macrophages in the tumor-draining lymph nodes. This local immune activation can further reshape the TME, promoting antigen presentation and suppressing immunoregulatory populations, thus enhancing anti-tumor efficacy in a murine melanoma model. These findings establish ACTIVATE as a modular platform for orchestrating coordinated immune responses to improve ACT outcomes in solid tumors.