表达叉头盒 P3 (Foxp3) 的调节性 T 细胞 (Treg) 是受控免疫反应的守护者，可预防自身免疫性疾病的发展。然而，在肿瘤背景下，它们数量的增加会抑制抗肿瘤免疫反应，这表明了解其功能和稳定性背后的机制的重要性。代谢重编程可以影响 Foxp3 调节，从而影响 Treg 抑制功能和适应性。在这里，我们进行了代谢 CRISPR/Cas9 筛选，并确定了 Foxp3 的新型候选正和负代谢调节因子。在正调节因子中，我们发现，针对 Tregs 中的 GDP-岩藻糖转运蛋白 Slc35c1 以及更广泛的岩藻糖基化，会损害其体外和体内的增殖和抑制功能，导致肿瘤微环境 (TME) 的改变并损害肿瘤进展和促肿瘤免疫反应。岩藻糖基化的药理抑制主要通过靶向 Tregs 来抑制肿瘤免疫抑制，从而减少肿瘤生长。为了在人类中证实这些发现，我们根据岩藻糖基化 (Fuco) 相关基因的表达对结直肠癌 (CRC) 患者的肿瘤 Tregs 进行了聚类。研究发现，与 FucoHIGH Tregs 相比，FucoLOW Tregs 表现出更强的免疫原性。此外，FucoLOW 特征的丰富（主要源自 Tregs）与黑色素瘤患者更好的预后和对免疫检查点阻断的反应相关。总之，Slc35c1 依赖性岩藻糖基化能够调节 Tregs 的抑制功能，测量其在 Tregs 中的表达可能为癌症患者有用的生物标志物模型铺平道路。

Forkhead box P3 (Foxp3)-expressing regulatory T cells (Tregs) are the guardians of controlled immune reactions and prevent the development of autoimmune diseases. However, in the tumor context, their increased number suppresses antitumor immune responses, indicating the importance of understanding the mechanisms behind their function and stability. Metabolic reprogramming can affect Foxp3 regulation and, therefore, Treg suppressive function and fitness. Here, we performed a metabolic CRISPR/Cas9 screen and pinpointed novel candidate positive and negative metabolic regulators of Foxp3. Among the positive regulators, we revealed that targeting the GDP-fucose transporter Slc35c1, and more broadly fucosylation, in Tregs compromises their proliferation and suppressive function both in vitro and in vivo, leading to alteration of the tumor microenvironment (TME) and impaired tumor progression and pro-tumoral immune responses. Pharmacologic inhibition of fucosylation dampened tumor immunosuppression mostly by targeting Tregs, thus, resulting in reduced tumor growth. In order to substantiate these findings in humans, tumoral Tregs from colorectal cancer (CRC) patients were clustered based on the expression of fucosylation (Fuco)-related genes. FucoLOW Tregs were found to exhibit a more immunogenic profile compared to FucoHIGH Tregs. Furthermore, an enrichment of a FucoLOW signature, mainly derived from Tregs, correlated with better prognosis and response to immune checkpoint blockade in melanoma patients. In conclusion, Slc35c1-dependent fucosylation is able to regulate the suppressive function of Tregs, and measuring its expression in Tregs might pave the way towards a useful biomarker model for cancer patients.