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 Mg²⁺ 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 Mg²⁺ and IL12. Locally released Mg²⁺ 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 Ca²⁺-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.

Nano-aluminum adjuvants  /  Interleukin-12 tumor therapy  /  Acidosis alleviation  /  Mg²⁺ supplementation  /  Cytotoxic T cell activation  /  Cytotoxic T cell infiltration  /  Cytotoxic T cell immune exhaustion  /  Tumor microenvironment