Dhar Subhanki, Sarkar Tania, Bose Sayantan, Pati Subhadip, Chakraborty Dwaipayan, Roy Dia, Panda Abir K, Guin Aharna, Mukherjee Sumon, Jana Kuladip, Sarkar Diptendra K, Sa Gaurisankar
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Department of Surgery, IPGMER-SSKM Hospital, Kolkata, India.
Immunology. 2025 Mar;174(3):296-309. doi: 10.1111/imm.13887. Epub 2024 Dec 30.
The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4 Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.
肿瘤微环境以多种方式影响宿主免疫系统，生长中的肿瘤与之相互作用以促进免疫逃逸。其中一种影响方式是操纵肿瘤微环境中细胞的代谢过程。生长中的肿瘤会大量摄取葡萄糖（肿瘤部位可获得的主要能量来源），并通过瓦伯格效应产生乳酸。在这样恶劣的环境中，肿瘤浸润免疫细胞在代谢上无法存活。另一方面，肿瘤浸润性CD4调节性T细胞（Treg细胞）适应了一种替代能量产生系统，通过下调葡萄糖代谢基因并上调脂肪酸代谢基因，从竞争激烈的葡萄糖代谢途径转向脂肪酸代谢途径。脂肪酸代谢途径的关键成分——具有高水平脂肪酸清道夫受体CD36的Treg细胞，有助于这种代谢转变。当脂肪酸代谢途径被破坏时，Treg细胞的形成受到阻碍，这表明该途径对Treg细胞的发育是必要的。Treg细胞谱系特异性转录因子FOXP3通过诱导CD36转录来调节脂肪酸代谢。高脂饮食增强了Treg细胞的发育，同时抑制了抗肿瘤免疫，而低脂饮食则抑制了Treg细胞的发育。肿瘤浸润性Treg细胞代谢的改变使其能够在恶劣的肿瘤微环境中快速生成和存活，从而促进癌症进展。有趣的是，与高脂饮食喂养的小鼠相比，低脂饮食喂养的小鼠化疗后的预后更好。因此，在化疗期间改变饮食组成可能会实现化疗的最大疗效，为未来癌症治疗提供了一个有前景的方向。
