TME/NIR Dual‐Responsive Zinc‐Based Targeted Nanoagonist for Multimodal Amplification of STING‐Mediated Cancer Immunotherapy

ABSTRACT The precise activation of the cGAS‐STING pathway for effective tumor immunotherapy remains a significant challenge due to the complexity of immune responses and tumor microenvironment (TME) limitations. Here, a multifunctional nanoagonist, cRGD‐PDA/ZIF8@ICG/TPT (cDZ@IP), was developed to realize nano‐metabolite–driven multimodal synergistic activation of the STING pathway and enhanced immune recognition. The agonist combines cRGD peptide‐targeted polydopamine‐coated zeolitic imidazolate framework‐8 with the photosensitizer indocyanine green and the chemotherapeutic drug topotecan. Upon near‐infrared laser irradiation, cDZ@IP degrades within the TME, generating high levels of reactive oxygen species, inducing mitochondrial stress, and releasing endogenous mitochondrial DNA. Additionally, topotecan enhances DNA damage accumulation by inhibiting nuclear DNA repair. Zn 2 + released from the agonist further amplifies cGAS‐STING pathway activation, thereby ensuring a robust immune response. The mild photothermal therapy‐induced immunogenic cell death promotes the initiation of antitumor immunity, while also enhancing the effectiveness of immune checkpoint blockade. In vivo studies show that cDZ@IP significantly inhibits primary and distant tumor growth and prevents lung metastasis, providing a promising strategy for STING pathway‐targeted cancer immunotherapy.