Persistent and Potent Anticancer Immunity Empowered by Manganese‐Coordinated STING‐Activating Microgels

ABSTRACT Activation of stimulator of interferon genes (STING) pathway represents a powerful strategy to generate potent immune responses for cancer immunotherapy, yet clinical translation is hindered by rapid drug clearance, suboptimal activation, and severe local and systemic toxicity. Herein, we report on manganese‐coordinated STING‐activating microgels (MSM) for safe, sustained, and synergistic activation of anticancer immunity, effectively annihilating various solid tumors. MSM shows efficient encapsulation (>90%) and gradual release of diABZI agonist and Mn 2+ over four weeks, affording cooperative and continuous activation of dendritic cells, MHC upregulation, and proinflammatory cytokine production. Notably, a single intratumoral dose of MSM elicits durable innate and adaptive immunity, remarkably eradicating multiple murine tumors and establishing immune memory against rechallenge. Repurposed as an embolic agent, MSM suppresses orthotopic rabbit VX2 liver tumors and lung metastases through transarterial immunoembolization, demonstrating translational potential across species and tumor models.