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

Radiotherapy is an important anticancer 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 with ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a marked increase of tumor necrosis factor-α- and inducible nitric oxide synthase-producing inflammatory macrophages in local and distal nonirradiated 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 interferon-γ are crucial for increasing inflammatory macrophage levels in IR- and RA-treated tumors. Whereas CD8+ T cells are required for the antitumor response to IR, CD4+ T cells are required for the effectiveness of the IR + RA combination. Combination treatment with RA enhanced the abscopal response when radiation and programmed cell death-ligand 1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR + RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.