Manganese in metalloimmunotherapy: From molecular targets to materials engineering and translational therapeutics

Immunotherapy harnesses immune cells [1], [2], [3], antibodies [4], [5] and vaccines [6], [7] to enhance the immune response, demonstrating efficacy towards a broad spectrum of illnesses, together with malignancies and infectious illnesses. Over time, immunotherapy has developed into a various therapeutic paradigm, akin to immune checkpoint inhibitors [8], [9], [10] and chimeric antigen receptor (CAR) T-cell remedy [11], [12], [13]. These developments have considerably expanded remedy choices for sufferers, offering renewed hope for sufferers. Nevertheless, important challenges stay of their scientific software, together with restricted selectivity, efficacy, in addition to dangers of immunotoxicity and excessive prices.

To handle these challenges, metalloimmunotherapy has emerged as a promising technique by leveraging immune regulatory mechanisms mediated by steel ions. This progress is pushed by rising insights into the pivotal roles of steel ions in modulating immune responses. Steel ions are integral to immune pathway regulation [14], distinguishing metalloimmunotherapy from different immunotherapeutic approaches. Steel immunology highlights the immunomodulatory capabilities of steel ions, akin to: (1) cGAS-STING signalling (Mn²⁺and Zn²⁺) [15], [16]; (2) pathogen–host interactions (Fe^2+/3+, Zn²⁺, Mn²⁺ and Cu²⁺) [17], [18]; (3) T cell activation (Ca²⁺) [19], [20]; (4) stemness upkeep (Ok⁺) [21], [22], and (5) activation of inflammasome (Ok⁺, Ca²⁺ and Na⁺) [23], [24], [25]. These discoveries have catalyzed the event of metalloimmunotherapy, a subject devoted to exploiting steel ions for focused immunomodulation [26], [27]. Collectively, these advances have established a basis for designing steel ion-based immunotherapeutics with enhanced precision and efficacy. Amongst these steel ions, manganese (Mn²⁺) has garnered specific consideration resulting from its a number of roles in sustaining physiological homeostasis and exerting immunomodulatory results, together with innate immune activation, antimicrobial exercise, and antitumor responses.

Manganese, a necessary inorganic micronutrient, is current in human tissues at concentrations starting from 0.3 to 2.9 mg/kg, primarily in its divalent type (Mn²⁺). As a necessary structural cofactor of metalloenzymes and catalytic activator of varied enzymes, together with superoxide dismutase 2 (SOD2), glutamine synthetase (GS), and arginase[28], Mn²⁺ mediates essential physiological capabilities in copy, neurodevelopment, and antioxidant protection by way of its enzymatic actions [29], [30], [31]. Mn²⁺ orchestrates each immune surveillance (for compromised host cells) and innate immune defenses (towards pathogens) by way of cGAS-STING activation. Particularly, it serves as a essential cofactor for cyclic GMP-AMP synthase, enhancing its sensitivity to broken self-DNA to eradicate aberrant cells, whereas additionally potentiating detection of pathogen-derived DNA throughout infections [15], [32]. Past its immunomodulatory function, Mn²⁺ exerts direct antimicrobial and antitumor results by way of catalytic era of cytotoxic reactive oxygen species (ROS) [33], [34], [35], [36], [37], [38], [39], [40], whereas concurrently enhancing antitumor immunity through a number of pathways: (1) selling antigen presentation to prime adaptive immunity, (2) augmenting NK cell-mediated cytotoxicity, and (3) rising tumor infiltration of reminiscence CD8 + T cells. These immunostimulatory properties synergize remarkably with combinatorial therapies, together with photothermal/photodynamic modalities and immune checkpoint blockade, providing a multifaceted method to potentiate therapeutic outcomes [41], [42], [43], [44], [45].

Regardless of being a necessary hint factor, Mn²⁺ faces important challenges for systemic therapeutic functions, together with neurotoxicity, a slim therapeutic window, poor focusing on specificity, and complicated pharmacokinetics. To beat these limitations, the event of superior supply programs able to exact focusing on, managed launch, and optimized pharmacokinetics is essential for Mn²⁺-based therapeutics. Present methods leverage nanotechnology and stimuli-responsive supplies to reinforce therapeutic outcomes [46], [47].

Though important progress has been made in elucidating the mechanisms of manganese immunotherapy and its functions in oncology, its broader translation into scientific immunotherapy stays constrained. As outlined in Fig. 1, this assessment systematically summarizes: (1) the mechanistic foundations of Mn²⁺-mediated immunomodulation; (2) superior materials design methods; (3) rising functions in antiviral, antimicrobial, and antitumor immunity. Past the scope of this schematic, the assessment additionally critically addresses the important thing challenges and future instructions pivotal for increasing the therapeutic potential of manganese.