RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Traditional Chinese medicine remodels the immune microenvironment of colorectal cancer: mechanisms and therapeutic perspectives.
Traditional Chinese medicine remodels the immune microenvironment of colorectal cancer: mechanisms and therapeutic perspectives.
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结直肠癌(CRC)是消化道常见的恶性肿瘤,其发生发展与肿瘤免疫微环境失调密切相关。CRC免疫微环境由效应免疫细胞、免疫抑制细胞、炎症介质、免疫检查点通路、基质细胞、细胞外基质、肠道菌群及微生物代谢产物组成,其病理特征包括免疫识别与效应免疫功能受损、免疫抑制增强、细胞外基质重塑介导的免疫排斥、炎症与免疫检查点信号失调,以及肠道菌群与代谢紊乱。中医药(TCM)以多成分、多靶点、多层次调控为特点,在CRC免疫微环境研究中显示出潜在价值。目前临床前研究表明,中药单体化合物及生物活性成分、单味中药、中药复方和中成药可能通过恢复抗原呈递、促进树突状细胞成熟、增强效应T细胞应答和NK 细胞活性来改善免疫识别与效应免疫功能;也可能抑制免疫抑制细胞、调控免疫检查点及炎症相关信号,并通过诱导免疫原性肿瘤细胞死亡增强抗肿瘤免疫。
此外,中医药还可能通过调控癌相关成纤维细胞介导的基质重塑,以及调节肠道菌群、微生物代谢产物和肿瘤免疫代谢,减轻免疫抑制与免疫排斥。在一些临床前模型中,这些效应增强了免疫检查点阻断的抗肿瘤疗效,为TCM联合免疫治疗的进一步机制验证和临床研究提供了实验支持。
然而,目前的证据仍以临床前为主,尚需进一步的临床验证以及对生物利用度、安全性和药物相互作用的评估。本综述总结了CRC免疫微环境的组成和病理特征,并讨论了TCM介导的免疫调节的最新进展。
同时,还审视了当前的机制证据及其局限性,以期为进一步的机制验证、临床研究设计和转化研究提供参考。
Colorectal cancer (CRC) is a common malignancy of the digestive tract, and its initiation and progression are closely associated with dysregulation of the tumor immune microenvironment. The CRC immune microenvironment consists of effector immune cells, immunosuppressive cells, inflammatory mediators, immune checkpoint pathways, stromal cells, the extracellular matrix, the gut microbiota, and microbial metabolites. Its pathological features include impaired immune recognition and effector immunity, enhanced immunosuppression, extracellular matrix remodeling-mediated immune exclusion, dysregulated inflammatory and immune checkpoint signaling, and disturbances in gut microbiota and metabolism.
Traditional Chinese medicine (TCM), characterized by multicomponent, multitarget, and multilevel regulation, has shown potential value in research on the CRC immune microenvironment. Current preclinical studies suggest that TCM-derived isolated compounds and bioactive constituents, single herbs, Chinese herbal formulas, and Chinese patent medicines may improve immune recognition and effector immune function by restoring antigen presentation, promoting dendritic cell maturation and enhancing effector T-cell responses and natural killer cell activity.
These interventions may also inhibit immunosuppressive cells, modulate immune checkpoint and inflammation-related signaling, and enhance antitumor immunity by inducing immunogenic forms of tumor cell death.
In addition, TCM may alleviate immunosuppression and immune exclusion by modulating stromal remodeling mediated by cancer-associated fibroblasts and regulating the gut microbiota, microbial metabolites, and tumor immunometabolism. In some preclinical models, these effects enhanced the antitumor efficacy of immune checkpoint blockade and provided experimental support for further mechanistic validation and clinical studies of TCM combined with immunotherapy.
However, current evidence remains predominantly preclinical, and further clinical validation and assessment of bioavailability, safety, and drug interactions are needed. This review summarizes the composition and pathological features of the CRC immune microenvironment and discusses recent advances in TCM-mediated immune modulation. It also examines current mechanistic evidence and its limitations to inform further mechanistic validation, clinical study design, and translational research.
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