Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper.

中文翻译：

---

FOXP3（失）稳定性和癌症免疫治疗

调节性 T 细胞 (Treg) 的失调在炎症和自身免疫性疾病以及癌症的背景下进行了描述。叉头框 P3 (FOXP3) 是一种转录因子，其活性是 Treg 身份的指标。 FOXP3 诱导肿瘤内 Tregs 的代谢多功能性，因此其缺陷会介导 Treg 不稳定，甚至导致效应 T 细胞表型的获得。 FOXP3 失调和缺陷发生在泛素化、甲基化和可能的乙酰化时。 PTEN、雷帕霉素复合物 2 (mTORC2) 哺乳动物靶点和伏隔核相关蛋白 1 (NAC1) 的刺激剂，以及 B 淋巴细胞诱导成熟蛋白 1 (Blimp-1)、Deltex1 (DTX1) 和泛素的抑制剂特异性肽酶 22 (USP22) 被认为会阻碍 FOXP3 的稳定性，并促进其下调和进一步 Treg 耗竭。值得注意的是，Treg 亚群对 FOXP3 的依赖程度不同，这表明并非所有的 Treg 都严格依赖于 FOXP3，并且可能不同来源的 Treg 依赖于不同的 FOXP3 稳定性调节因子。本综述的重点是目前对 FOXP3 的理解、其在 Tregs 中的活性以及肿瘤微环境 (TME) 内不同调节因子的影响。 FOXP3 靶向在癌症免疫治疗中的意义是本文的另一个重点。