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While immunotherapy strategies such as immune checkpoint inhibition and adoptive T cell therapy have become commonplace in cancer therapy, they suffer from limitations, including lack of patient response and toxicity. To wield the maximum potential of the immune system, cancer immunotherapy must integrate novel targets and therapeutic strategies with potential to augment clinical efficacy of currently utilized immunotherapies. PTPN22, a member of the protein tyrosine phosphatase (PTP) superfamily that downregulates T cell signaling and proliferation, has recently emerged as a systemically druggable and novel immunotherapy target. This review describes the basics of PTPN22 structure and function and provides comprehensive insight into recent advances in small molecule PTPN22 inhibitor development and the immense potential of PTPN22 inhibition to synergize with current immunotherapies. It is apparent that small molecule PTPN22 inhibitors have enormous potential to augment efficacy of current immunotherapy strategies such as checkpoint inhibition and adoptive cell transfer. Nevertheless, several constraints must be overcome before these inhibitors can be applied as useful therapeutics, namely selectivity, potency, and  in vivo  efficacy.

PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy