From Coordination Chemistry to Immune Modulation: Rational Design of Next‐Generation Mn 2+ ‐Based Immunomodulators

ABSTRACT Mn 2+ has emerged as a potent immunostimulatory modulator capable of activating cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and other innate immune signaling pathways. Consequently, Mn 2+ induces type I interferon responses, and promotes robust antitumor and antiviral immunity. Recent advances have revealed that Mn 2+ ‐protein coordination fundamentally shapes innate immune signaling and primes downstream adaptive immunity. Deciphering these molecular mechanisms is critical for understanding Mn 2+ –mediated immune modulation and for guiding the rational design and engineering of next‐generation Mn 2+ ‐based immunomodulators. In this perspective, we systematically examine the Mn 2+ coordination with diverse ligands, including inorganic anions, small molecules, polymers, and proteins, and their roles in regulating immune signaling, therapeutic efficacy, and nanosystem engineering. We further discuss design principles for data‐driven engineering Mn 2+ ‐based immunomodulators with precise spatiotemporal control over biodistribution and bioavailability, selective activation of immune signaling pathways, and improved therapeutic efficacy, biosafety, and clinical translatability. Overall, this perspective establishes a fundamental concept of “coordination‐mediated immune modulation”, advancing the emerging fields of metalloimmunology and metalloimmunotherapy.