Iron consumption strengthens anti-tumoral STING activation mediated by manganese-based nanoparticles

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, as an important part in innate immunity, has recently emerged as a promising target for improving tumor therapy. Manganese ions (Mn²⁺) are an emerging agonist in the cGAS-STING pathway with multifaceted advantages, however manganese-based nanoparticles alone as the Mn²⁺ source have shown limited activity in eliciting anti-tumor immune responses compared to conventional organic STING agonists, and the underlying mechanism of the suboptimal efficiency remains unclear. Here, we demonstrate that intratumoral iron ions attenuate manganese-induced anti-tumor STING activation, and that the utilization of deferoxamine (DFO), an iron chelator that depletes intratumoral iron ions, effectively increases the intracellular accumulation of Mn²⁺ and thus promoted the STING activation efficiency of a hyaluronic acid modified manganese carbonate-silica hybrid nanoparticle (DS@Mn-H) in macrophages. The mechanism study suggests that the addition of DFO inhibited the expression of ferroportin (FPN), which serves as a Mn²⁺ exporter to reduce intracellular Mn²⁺ level. The synergistic effect of DS@Mn-H and DFO achieved excellent anti-tumor activities in a mouse colon carcinoma model. This work provides new insights on improving the Mn-based metallo-immunotherapy of cancer.