CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Laboratory for Marine drugs and biological products, Pilot National Laboratory for Marine Science and Technology, Qingdao, China.
Int J Biol Macromol. 2022 Dec 1;222(Pt A):562-572. doi: 10.1016/j.ijbiomac.2022.09.201. Epub 2022 Sep 25.
Chemotherapy resistance is one of the most critical challenges in colorectal cancer (CRC) treatment. The occurrence and development of chemotherapy resistance closely related to the tumor immune microenvironment (TIME). As the most important immunosuppressive immune cells infiltrating into the TIME, macrophages are essential for chemotherapy resistance in CRC treatment. In this study, we found that a kind of fucoidan (FPS1M) induced macrophages differentiation to the M1 phenotype, and this transformation promoted cancer cells apoptosis both in vitro and in vivo. TNFα is a key mediator of FPS1M-induced tumorcidal activity of macrophages. Mechanistically, as a stimulator of TLR4, FPS1M enhanced macrophages glycolysis and regulated macrophages differentiation to the M1 phenotype by the activation of TLR4 mediated PI3K/AKT/mTOR signaling axis. In addition, FPS1M improved the immunosuppressed tumor microenvironment by increasing the infiltration of M1 macrophages in tumor tissue, which was conducive to improving the sensitivity of tumor to chemotherapy. Collectively, our findings demonstrated that FPS1M has the great potential to be used in tumor immunotherapy. The results also suggested that the combination of FPS1M with capecitabine is an alternative therapy method for colon cancer.
化疗耐药性是结直肠癌 (CRC) 治疗中最关键的挑战之一。化疗耐药性的发生和发展与肿瘤免疫微环境 (TIME) 密切相关。作为浸润 TIME 的最重要的免疫抑制性免疫细胞，巨噬细胞在 CRC 治疗中的化疗耐药性中起关键作用。在这项研究中，我们发现一种岩藻聚糖 (FPS1M) 诱导巨噬细胞向 M1 表型分化，这种转化促进了体外和体内癌细胞的凋亡。TNFα 是 FPS1M 诱导巨噬细胞杀伤肿瘤活性的关键介质。在机制上，作为 TLR4 的激动剂，FPS1M 通过激活 TLR4 介导的 PI3K/AKT/mTOR 信号通路增强巨噬细胞糖酵解，并调节巨噬细胞向 M1 表型分化。此外，FPS1M 通过增加肿瘤组织中 M1 巨噬细胞的浸润来改善免疫抑制的肿瘤微环境，这有利于提高肿瘤对化疗的敏感性。总之，我们的研究结果表明 FPS1M 具有很大的潜力用于肿瘤免疫治疗。这些结果还表明，FPS1M 与卡培他滨联合使用是结肠癌的一种替代治疗方法。
