糖类能促进脑内多巴胺分泌，故而高糖的饮食总是能给人带来更多的幸福感[1]。近年来，果葡糖浆、高果糖玉米糖浆类调味剂的使用量大大增加。果糖是葡萄糖的一种同分异构体，个人日常所摄入果糖总量的40~60%来源于水果、蜂蜜以及蔗糖；另一主要来源是由淀粉水解为葡萄糖后，葡萄糖通过多元醇途径转化为果糖。

    多项研究发现，果糖的过量摄入与肥胖、糖尿病和脂肪肝等代谢性疾病密切相关[2]。对于肿瘤发生发展，近日，重庆医科大学团队证实了高果糖在小鼠模型中能促进肝癌进展[3]；也有团队揭示了在小鼠模型中，果糖代谢可促进肠道肿瘤发生肝转移[4]。以上研究揭示了果糖对于肿瘤细胞生长的促进作用，但是果糖对肿瘤免疫的影响亟待揭示。

    2023年10月19日，上海交通大学医学院在Cell Metabolism上发表题为"Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses"的研究论文。上海交通大学医学院上海市免疫学研究所博士生张月榕、副研究员于晓彦和技术员包汝娟为该论文的共同第一作者；上海交通大学医学院邹强、孙加源、赵任和叶幼琼研究员为该论文的共同通讯作者。该研究揭示了一条免疫内分泌通路：果糖-脂肪细胞-瘦素- CD8+ T细胞轴，描述了膳食果糖在塑造脂肪细胞代谢以启动抗肿瘤CD8+ T细胞反应中的关键作用，提示该免疫内分泌通路潜在的癌症免疫治疗方案可能性。

      研究团队通过饲喂小鼠高果糖饲料并向小鼠接种皮下肿瘤发现，果糖饲喂组小鼠肿瘤生长更缓慢，且小鼠生存时间显著延长。结合单细胞测序、多种敲除鼠模型以及大数据分析，研究团队发现在果糖饲喂下，小鼠肿瘤微环境中的CD8+ T细胞耗竭减少，增殖更多，且细胞因子IFN-γ分泌增多。通过蛋白芯片对血清中炎症相关蛋白进行分析发现，关键在于一种脂肪因子——瘦素的含量发生了改变。果糖通过诱导了脂肪细胞中mTORC1依赖性瘦素的产生，增加了血清和肿瘤微环境中瘦素的水平，进而增强小鼠抗肿瘤免疫应答水平。

     研究团队进一步从肺癌患者肿瘤样本和血液样本中发现，肺癌患者血浆中果糖浓度与瘦素水平呈正相关，且血浆中瘦素水平和肿瘤微环境内抗肿瘤CD8+ T细胞功能提升相关。

英文摘要:   Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.

    In this study, the authors show that feeding mice with a high-fructose diet improved antitumor CD8+ T cell responses and delayed tumor growth. Fructose consumption triggered mTORC1-dependent leptin production in adipocytes and increased leptin levels in serum and tumor tissue, which were critical for the enhanced antitumor immunity observed. Importantly, high plasma leptin levels were correlated with augmented antitumor T cell activity in patients with lung cancer. Our data suggest the importance of dietary fructose in directing adipocyte metabolism to shape CD8+ T cell immune responses and control tumor growth. These findings suggest targetable relevance of the fructose-leptin axis in immunotherapy for lung cancer.

Highlights

•Dietary fructose can enhance antitumor CD8+ T cell immune responses

•Dietary fructose can prevent the transition of CD8+ T cells to terminal exhaustion

•Adipocyte-derived leptin is critical for CD8+ T cell-dependent tumor control

•Fructose-initiated leptin production in adipocytes relies on mTORC1 activation

原文链接：https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00367-4   

DOI:  https://doi.org/10.1016/j.cmet.2023.09.011 

全文：https://www.sciencedirect.com/science/article/abs/pii/S1550413123003674   

参考文献:

1. Edwin Thanarajah, S., et al., Habitual daily intake of a sweet and fatty snack modulates reward processing in humans. Cell Metab, 2023. 35(4): p. 571-584 e6.

2. Febbraio, M.A. and M. Karin, "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab, 2021. 33(12): p. 2316-2328.

3. Zhou, P., et al., High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab, 2023. https://doi.org/10.1016/j.cmet.2023.09.009 

4. Bu, P., et al., Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. Cell Metab, 2018. 27(6): p. 1249-1262 e4.