T lymphocyte membrane bionic nanomedicine synergizes with radiotherapy for enhancing Mg ²⁺ -mediated tumor metallo-immunotherapy and preventing recurrence

<b>Background and Aim:</b> Magnesium ion (Mg²⁺)-mediated metallo-immunotherapy effectively promotes the activation of memory T cells, thereby helping to mitigate tumor recurrence following traditional treatments such as radiotherapy (RT). However, factors such as the acidity of the tumor microenvironment, along with the upregulated expression of immune checkpoints induced by RT and Mg²⁺, may compromise its therapeutic efficacy. <b>Material and Methods:</b> In this work, we developed a T cell membrane-coated, hemin-loaded magnesium carbonate nanomedicine (designated as THM). Following intravenous injection, THM catalyzes the hydrogen peroxide generated during RT to induce a burst of reactive oxygen species (ROS), thereby producing a tumor vaccine that promotes dendritic cell maturation and T cell activation. Simultaneously, THM reacts with H⁺ to mitigate the acidic tumor microenvironment while releasing Mg²⁺, which further enhances the generation and activation of central memory T cells (Tcm) to confer long-term anti-tumor immunity following RT. <b>Results:</b> RT combined with Mg²⁺ treatment upregulates PD-L1 expression in tumor cells. Notably, the PD-1 protein on THM can competitively bind to PD-L1, thereby mitigating the side effects associated with the combined therapy. <i>In vitro</i> and <i>in vivo</i> data confirm that this combinatorial therapy boosts Tcm-mediated antitumor activity, mitigates treatment-induced immune suppression, and potently prevents tumor recurrence. <b>Conclusions:</b> This work provides critical insights for the clinical translation of antitumor immunotherapy.