CD4⁺ Regulatory T Cells in Human Cancer: Subsets, Origin, and Molecular Regulation

CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Treg) play major roles in the maintenance of immune tolerance, prevention of inflammation, and tissue homeostasis and repair. In contrast with these beneficial roles, Tregs are abundant in virtually all tumors and have been mechanistically linked to disease progression, metastases development, and therapy resistance. Tregs are thus recognized as a major target for cancer immunotherapy. Compared with other sites in the body, tumors harbor hyperactivated Treg subsets whose molecular characteristics are only beginning to be elucidated. Here, we describe current knowledge of intratumoral Tregs and discuss their potential cellular and tissue origin. Furthermore, we describe currently recognized molecular regulators that drive differentiation and maintenance of Tregs in cancer, with a special focus on those signals regulating their chronic immune activation, with relevant implications for cancer progression and therapy.