The cGAS-STING pathway represents a crucial DNA-sensing mechanism that has shown promise as a target for overcoming immunoresistance in solid tumors. Mn2+ and Zn2+ 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 Mn2+/PTX and Zn2+/Fe3+/DOX are co-delivered to tumor successfully, leading to the effective synergy between dsDNA generation by chemo-drugs and cGAS sensitization by Mn2+ and Zn2+. This efficiently activates the cGAS-STING pathway, thereby inducing the anti-tumor immune response and effectively inhibiting tumor growth, recurrence, and metastasis.

NCP/polymer nano-hybrids can successfully co-deliver metal ions and chemotherapeutic drugs to the tumor sites, leading to the effective synergy between dsDNA generation by chemo-drugs and cGAS sensitization by Mn2+ and Zn2+. This results in the efficient activation of cGAS-STING pathway, thereby inducing the anti-tumor immune response and effectively inhibiting tumor growth, recurrence, and metastasis.