Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H₂O₂. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy.

Myeloid checkpoint blockade as monotherapy often yields limited benefit, suggesting that multiple inhibitory pathways cooperatively sustain myeloid immunosuppression in the tumor microenvironment. However, strategies to concurrently target multiple myeloid checkpoints remain challenging. Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble LILRA/B family member with unclear immunoregulatory function. In this study, we show that LILRA3 is significantly reduced in the serum and tumor tissues of patients with cancer, and its systemic levels positively correlate with cytotoxic T-cell infiltration and improved survival. LILRA3 suppresses immunosuppressive myeloid cells, enhances proinflammatory cytokine production, and inhibits M2 macrophage polarization, thereby indirectly promoting T-cell proliferation. Mechanistically, LILRA3 binds to LILRB4 and multiple endogenous LILRB ligands, blocking downstream inhibitory signaling. LILRA3 restrains tumor growth in myeloid-specific LILRB2- and LILRB4-transgenic mice and in humanized mouse models. These findings identify LILRA3 as a natural multi-LILRB signaling antagonist that counteracts myeloid-driven immunosuppression and highlight its potential as a therapeutic immune modulator.