Manganese mediates nucleoplasm distribution of cGAS to enhance systemic antitumor immunity and drive abscopal effect

Abscopal effect remains rare and clinically unpredictable because of immunosuppressive mechanisms and inadequate immune activation. This phenomenon may stem from cyclic GMP-AMP synthase (cGAS) sequestration within the nucleus, where high-affinity nucleosome-DNA interactions potently suppress cGAS activation. Our study elucidates the capacity of manganese (Mn²⁺) to overcome this limitation through cytoplasmic relocalization and potentiation of cGAS activity, thereby enabling abscopal responses. We demonstrated that Mn²⁺ disrupts nucleosomal constraints on cGAS, permitting robust double-stranded DNA (dsDNA) sensing and activation. This molecular reprogramming amplifies cytosolic cGAS-STING signaling cascades and IFN-I production in irradiated tumors, potentiating systemic antitumor immunity. Notably, Mn²⁺ exerts direct immunostimulatory effects on adaptive immunity by activating T cells, creating synergistic therapeutic benefits. Preliminary clinical observations in advanced metastatic malignancies have demonstrated that Mn²⁺ augments abscopal responses during radiotherapy. These findings mechanistically delineate the dual role of Mn²⁺ in modulating tumor-intrinsic cGAS-STING activation and immune effector functions, supporting its therapeutic application in combination with radioimmunotherapy regimens to overcome tumor microenvironment immunosuppression and induce abscopal effect.