A Multi‐Functional Nanoadjuvant Coupling Manganese with Toll‐Like 9 Agonist Stimulates Potent Innate and Adaptive Anti‐Tumor Immunity

Abstract The effectiveness of Toll‐like 9 agonists (CpG) as an adjuvant for tumor immunotherapy is restricted due to their insufficient ability to activate anti‐tumor immunity. To address that, the common nutrient metal ions are explored (Mn 2+ , Cu 2+ , Ca 2+ , Mg 2+ , Zn 2+ , Fe 3+ , and Al 3+ ), identifying Mn 2+ as a key enhancer of CpG to mediate immune activation by augmenting the STING‐NF‐κB pathway. Mn 2+ and CpG are then self‐assembled with epigallocatechin gallate (EGCG) into a nanoadjuvant MPN/CpG. Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma‐bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2‐type tumor‐associated macrophages (TAMs) to an M1‐type and boosting intra‐tumoral infiltration of CD8 + /CD4 + T lymphocytes and DCs. Furthermore, compared to free CpG, MPN/CpG exhibits heightened accumulation in lymph nodes, enhancing CpG uptake and DC activation, consequently inducing significant antigen‐specific cytotoxic CD8 + T cell immune response and humoral immunity. In a prophylactic tumor‐bearing mouse model, MPN/CpG vaccination with OVA antigen significantly delays B16‐OVA melanoma growth and extends mouse survival. These findings underscore the potential of MPN/CpG as a multifunctional adjuvant platform to drive powerful innate and adaptive immunity and regulate TME against tumors.