All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages.

Radiotherapy (RT) is an important anti-cancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared to ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a dramatic increase of TNF-α- and inducible nitric oxide synthase (iNOS)-producing inflammatory macrophages in local and distal non-irradiated (distal) tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell-derived IFN-γ are crucial for increasing inflammatory macrophage levels in IR and RA treated tumors. Notably, whereas CD8 T cells are required for the antitumor response to IR, CD4 T cells are required for the effectiveness of the IR and RA combination. Combination treatment with RA enhanced the abscopal response when radiation and PD-L1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR plus RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.