Modulation of regulatory T cells by natural products in cancer

Tumor tolerance is known as a condition of systemic immune unresponsiveness or immunosuppression against cancers, in which malignant cells escape from the immune surveillance. Among the elements of immune tolerance orchestra, the CD4⁺CD25 + forkhead box protein3+ (Foxp3+) regulatory T cells (Tregs) have a great importance. Moreover, increased Treg populations and, particularly, reduced proportions of effector T cells to Tregs in tumor-infiltrating lymphocytes are closely linked to worse prognosis in different tumors. In the last years, several drugs for cancer immunotherapy have been developed with very promising results; however, different resistance mechanisms to immunotherapy may limit their effectiveness. Plant-derived natural agents are emerging as an innovative therapeutic field. Particularly, a number of phytochemicals, by altering diverse immune signaling pathways, have shown to possess immunomodulating features; hence, they have been tested in multiple cancer experimental models in order to contrast the tumor-induced immunosuppressive behavior, particularly Tregs-mediated immune evasion in the tumor microenvironment. In this review, recent advances on the anti-cancer effect of natural agents, either alone or in combination with traditional drugs, due to the modulation of classic Treg cells, have been resumed with the aim to guide researchers for their potential future clinical use.