Work

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

Year: 2025

Type: article

Abstract: 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 (Mn 2+ ) to overcome this limitation through cytoplasmic relocalization and potentiation of cGAS activity, thereby enabling abscopal responses. We demonstrated that Mn 2+ 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, Mn 2+ 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 Mn 2+ augments abscopal responses during radiotherapy. These findings mechanistically delineate the dual role of Mn 2+ 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.

Source: Cancer Letters

DOI: 10.1016/j.canlet.2025.218154