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.

放射疗法是一种重要的抗癌治疗方式，可激活先天性和适应性免疫反应。当全反式维甲酸 (RA) 与辐射一起给药时，我们观察到与单独的电离辐射 (IR) 或单独的 RA 相比具有更好的抗肿瘤反应。联合治疗的卓越抗肿瘤作用伴随着局部和远端未照射肿瘤中肿瘤坏死因子-α和可诱导一氧化氮合酶产生的炎性巨噬细胞的显着增加。炎性巨噬细胞通过在局部和远端肿瘤中诱导效应 T 细胞浸润和增强效应 T 细胞与调节性 T 细胞的比例，对联合治疗的疗效至关重要。T 细胞和 T 细胞衍生的干扰素-γ 对于增加 IR 和 RA 治疗的肿瘤中的炎性巨噬细胞水平至关重要。而 CD8⁺ T 细胞是对 IR 的抗肿瘤反应所必需的，CD4 ⁺ T 细胞是 IR + RA 组合的有效性所必需的。当辐射和程序性细胞死亡-配体 1 阻断一起使用时，与 RA 的联合治疗增强了远位反应。IR+RA联合治疗的抗肿瘤疗效需要炎性巨噬细胞和适应性免疫的协同正反馈回路。我们的研究结果为增强 IR 的局部和全身抗肿瘤作用提供了一种转化且相对无毒的策略。