NCP/polymer Nano‐Hybrids for Effective cGAS‐STING Activation and Cancer Immunotherapy

Abstract The cGAS‐STING pathway represents a crucial DNA‐sensing mechanism that has shown promise as a target for overcoming immunoresistance in solid tumors. Mn 2+ and Zn 2+ play crucial roles in innate immune sensing of cytosolic dsDNA, ultimately resulting in the activation of cGAS‐STING pathway. Unfortunately, efficient delivery of these metal ions to target cells remains a challenge, limiting their effectiveness in activating the STING pathway. Herein, a novel strategy based on nanoscale coordination polymer (NCP)/polymer nano‐hybrids is presented, which enables effective co‐delivery of metal ions and chemotherapeutics to tumor tissues, thereby activating the cGAS‐STING pathway to induce strong anti‐tumor immune responses. In this strategy, NCPs are water‐insoluble under physiological conditions, enabling efficient loading of metal ions while minimizing leakage in the bloodstream. In addition, designing the ligands of the NCPs to respond to different biological signals can enable rapid dissociation and metal ions/drugs release specifically at tumor sites. With this strategy, metal ion‐drug combinations such as Mn 2+ /PTX and Zn 2+ /Fe 3+ /DOX are co‐delivered to tumor successfully, leading to the effective synergy between dsDNA generation by chemo‐drugs and cGAS sensitization by Mn 2+ and Zn 2+ . This efficiently activates the cGAS‐STING pathway, thereby inducing the anti‐tumor immune response and effectively inhibiting tumor growth, recurrence, and metastasis.