Soft‐Drug‐Inspired MnSTF Nano‐Adjuvant for Safe and Synergistic cGAS–STING Activation in Tumor Immunotherapy

Abstract The activation of the stimulator of interferon genes (STING) pathway is a cutting‐edge strategy in tumor immunotherapy and has shown transformative potential in preclinical studies by inducing a type I interferon cascade and remodeling the tumor immune microenvironment. However, current STING agonists are limited by a narrow therapeutic window and substantial systemic toxicity, which significantly impedes their translational potential. To overcome these challenges, a novel self‐assembling nanoadjuvant, MnSTF, grounded in the soft‐drug design paradigm is designed. MnSTF is assembled through multidentate coordination between manganese ions (Mn 2+ ), which exhibit moderate STING‐activating activity, and the ENPP1 inhibitor STF‐1623, thereby achieving synergistic activation of the cGAS–STING signaling axis. In contrast to conventional small‐molecule STING agonists, MnSTF elicits no systemic inflammatory response at either therapeutic or supratherapeutic doses, demonstrating outstanding safety and biocompatibility. Furthermore, MnSTF profoundly reprograms the tumor immune microenvironment and, when coadministered with radiotherapy, mRNA vaccines, or protein antigens, induces robust antigen‐specific T cell responses and marked antitumor efficacy. Accordingly, by combining soft‐drug design with a dual‐targeted immunomodulatory mechanism, MnSTF effectively reconciles the efficacy–safety trade‐off of STING agonists in preclinical settings and expands the potential for precise immunoregulation via the STING pathway.