DJ-1 inhibition reshapes tumor microenvironment and potentiates immune checkpoint inhibitors.

Abstract

Immune checkpoint inhibitors (ICIs) can essentially treat cancer but only in a small subset of patients. Treatment strategies capable of effectively and robustly sensitizing refractory patients to ICIs represent a highly coveted yet unmet clinical need. In this study, we identified DJ-1 as a negative T cell regulator. DJ-1 knockout boosts antitumor immunity and significantly potentiates PD-1 and TIM-3 blockades in murine cancer models. Single-cell sequencing of tumor-infiltrating CD45⁺ cells revealed that DJ-1 deficiency indirectly activates T cells by reprogramming macrophages. Mechanistically, loss of DJ-1 increases reactive oxygen species (ROS) in macrophages, activating NF-κB/STAT3 signaling to promote differentiation into Cxcl9⁺ immune-stimulatory phenotypes while reducing immune-suppressive Spp1⁺ macrophages. Notably, this reprogramming may be stable across tumor microenvironments because the transplanted DJ-1-deficient macrophages maintain T cell-activating capacity. Pharmacological inhibition of DJ-1 by disulfiram markedly potentiated antitumor efficacy of PD-1 blockade. This designates DJ-1 as a promising target for overcoming immune checkpoint resistance and optimize combination therapies.