Interleukin 12-tethered nano-aluminum adjuvant orchestrates environmental immunomodulation to empower cytotoxic T cells against solid tumors

The immunosuppressive tumor microenvironment (TME) profoundly limits the therapeutic efficacy of CD8 + T cells in solid tumors. While cytokine therapies have shown promise in reactivating CD8 + T cells, they fail to address the common suppressive environmental attributes ( e.g. , acidosis and Mg 2+ deficiency) of solid tumors. Here, we report an innovative CD8 + T cell dual-functional modulator, interleukin-12-tethered nano-aluminum adjuvant (IL12@NAM), which counteracts the acidic TME to relieve acidosis and concurrently releases Mg 2+ and IL12. Locally released Mg 2+ and IL12 synergize in T cell infiltration and activation by promoting the phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, and enhance CD8 + T cell activation and functions via the Ca 2+ –nuclear factor of activated T cells 2 pathway. Furthermore, dual-functional IL12@NAM mitigates CD8 + T cell exhaustion by reducing PD1 and LAG3 expression and effectively increases the differentiation towards T helper 1 cells while decreasing regulatory T cells, creating a more favorable immune network for enhanced CD8 + T cell-mediated anti-tumor immunity. As a result, IL12@NAM has demonstrated potent therapeutic efficacy against advanced melanoma and breast cancer, and remarkably empowered adoptive T therapy of solid tumors. This study provides a paradigm for empowering cytotoxic T cells by reactivating and creating a sustainable immunoresponsive environment, offering a potential adjuvant strategy to enhance solid tumor therapy. IL12@NAM relieves tumor acidosis, releases Mg 2+ and IL12, reactivates CD8 + T cells while reducing exhaustion, thereby significantly promoting tumor-resident or adoptive CD8 T cells to attack and eliminate solid tumors.