The covalent modification of STAT1 cysteines by sulforaphane promotes antitumor immunity via blocking IFN-γ-induced PD-L1 expression

Abstract

Sulforaphane (SFN), a natural compound found in cruciferous vegetables, possesses well-documented antitumor properties. However, the precise functions and mechanisms of SFN in cancer suppression remain poorly understood. Here we provide evidence to demonstrate that SFN exerts more pronounced antitumor effects in immunocompetent mice compared to immunodeficient mice, suggesting the involvement of the host immune system in SFN-mediated tumor suppression. Furthermore, we reveal that SFN primarily acts through CD8⁺ cytotoxic T lymphocytes (CTLs) to enhance antitumor immunity by blocking the IFN-γ-mediated induction of PD-L1, a critical immune checkpoint receptor expressed in cancer cells. Importantly, our findings indicate that the suppression of PD-L1 expression by SFN is independent of the NRF2 protein stabilization pathway. Instead, SFN inhibits IFN-γ-mediated activation of STAT1, a key transcription factor involved in PD-L1 induction. Mechanistically, SFN covalently modifies specific cysteine residues (C155 and C174) on STAT1, resulting in the inhibition of its transcriptional activity. Notably, SFN-mediated downregulation of PD-L1 contributes to its antitumor immune effects, as demonstrated by enhanced anti-CTLA-4-mediated cytotoxicity. These findings indicate that SFN's antitumor effect extends beyond its direct cytotoxic properties, as it also actively engages the host immune system. This underscores SFN's immense potential as an immune-modulating agent in cancer therapy.