6‐Mercaptopurine potently inhibits recruitment of SHP2 by phosphorylated PD‐1 to inhibit PD‐1 signalling and enhance T cell function

Abstract

AbstractAntibody inhibitors that block PD‐1/PD‐L1 interaction have been approved for oncological clinics, yielding impressive treatment effects. Small molecules inhibiting PD‐1 signalling are at various stages of development, given that small molecular drugs are expected to outperform protein drugs in several ways. Currently, a significant portion of these small molecular inhibitors achieve this purpose by binding to a limited region of the PD‐L1 protein, thereby limiting the choice of chemical structures. Alternative strategies for developing small‐molecular PD‐1 inhibitors are urgently needed to broaden the choice of chemical structures. Here, we report that 6‐mercaptopurine (6‐MP) inhibits PD‐1 signalling, activates T cell function in vitro and in vivo and shrinks tumours by activating cytotoxic T cells. Mechanistically, 6‐MP potently inhibited PD‐1 signalling by blocking the recruitment of SHP2 by PD‐1. Considering that 6‐MP is a chemotherapeutic agent already approved by the FDA for childhood leukaemia, our work revealed a novel anti‐tumour mechanism for this drug and suggests that 6‐MP warrants further clinical evaluation for other tumour types.