However, a-CTLA-4 fails to counteract autocrine/paracrine TGFβ signaling, thereby resulting in NFAT/SMAD3-mediated upregulation of FOXP319 and a paradoxical increase in tumor-infiltrating Tregs in the TGFβ-enriched immune microenvironment found in the majority of cancers45. Here, SMAD3 is linked to neoplasm.