Cycloartenyl ferulate (CF) is abundant in brown rice with multiple biologic functions. It has been reported to possess antitumor activity; however, the related mechanism of action of CF has not been clarified. Herein, we unexpectedly uncover the immunological regulation effects of CF and its molecular mechanism. We discovered that CF directly enhanced the killing capacity of natural killer (NK) cells for various cancer cells in vitro. In vivo, CF also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma dependent on NK cells. In addition, CF promoted anticancer efficacy of the anti-PD1 antibody with improvement of tumor immune microenvironment. Mechanistically, we first unveiled that CF acted on the canonical JAK1/2-STAT1 signaling pathway to enhance the immunity of the NK cells by selectively binding to interferon γ receptor 1. Collectively, our results indicate that CF is a promising immunoregulation agent worthy of attention in clinical application in the future. Due to broad biological significance of interferon γ, our findings also provide a capability to understand the diverse functions of CF.

环阿魏酸（CF）在糙米中含量丰富，具有多种生物功能。据报道具有抗肿瘤活性；但CF的相关作用机制尚未阐明。在此，我们意外地揭示了CF的免疫调节作用及其分子机制。我们发现CF在体外直接增强自然杀伤（NK）细胞对多种癌细胞的杀伤能力。在体内，CF 还改善了依赖 NK 细胞的淋巴瘤清除和转移性黑色素瘤小鼠模型的癌症监测。此外，CF通过改善肿瘤免疫微环境提高了抗PD1抗体的抗癌功效。从机制上讲，我们首先揭示了CF作用于经典的JAK1/2-STAT1信号通路，通过选择性地与干扰素γ受体1结合来增强NK细胞的免疫力。总的来说，我们的结果表明CF是一种值得关注的有前途的免疫调节剂未来在临床应用中。由于干扰素 γ 具有广泛的生物学意义，我们的研究结果还提供了了解 CF 多种功能的能力。