Fig. 4: Putative therapeutic targeting of intratumoral T_reg cells.

Various molecules and/or pathways may be exploited to specifically target T_reg cells in the TME. Those targets expressed on the cell surface include the extracellular adenosine-producing enzymes CD39 and CD73, the T_reg cell activation marker 4-1BB, the receptor for VEGF (VEGF-R), the invariant chain of MHC-II (CD74), and the neutrophil-associated marker CD177. Additionally, some therapeutic targets are associated with cell signaling pathways, including the ATPase p97 in complex with its co-factor NPL4 (p97–NPL4 complex), the CARMA1–BCL10–MALT1 (CBM) complex, and LCK–ZAP–70 signaling downstream of TCR activation. The histone demethylase JMJD1C serves as an epigenetic modifier target to disrupt intratumoral T_reg cells. Transcription factors whose disruption is associated with impaired intratumoral T_reg cell function include FOXP3E2, FOXO1, c-REL (subunit of the canonical NF-κB complex), BATF, and TRPS1. Finally, direct metabolic targets include SREBP and FASN, associated with de novo fatty acid synthesis, and the fatty acid transporter CD36.