Abstract

Zinc homeostasis dysregulation is a significant feature in prostate cancer (PCa), characterized by a marked decrease in intracellular Zn 2+ concentration. High levels of Zn 2+ inhibit PCa cell proliferation, enhance drug sensitivity, and are closely linked to antitumor immune activation. Here, zeolitic imidazolate framework-8 (ZIF-8) was employed to encapsulate pyrithione (PT), a Zn 2+ ionophore, and cyclic diguanylate ( c -di-GMP), a STING agonist, followed by encapsulation with ovalbumin (OVA). In this nanoplatform (PT- c -di-GMP/OVA@ZIF-8), ZIF-8 degrades within the tumor microenvironment (TME) to release Zn 2+ . Upon cellular uptake, PT facilitates the intracellular transport of extracellular Zn 2+ . These Zn 2+ may act synergistically with c -di-GMP to stimulate the cGAS-STING pathway, while OVA promoting antigen presentation, collectively activating and amplifying antitumor immunity. Both in vitro and in vivo experiments demonstrated that PT- c -di-GMP/OVA@ZIF-8 effectively activates STING signaling and antitumor immune responses, leading to tumor regression. Furthermore, combination therapy with an anti-PD-L1 antibody further enhanced the antitumor efficacy. This study proposes a Zn 2+ overload and cGAS-STING pathway-based nanoplatform that activates robust antitumor immunity with a favorable safety profile, showing promise as a candidate strategy for PCa treatment.