ArticleFrontiers in immunology2026
Hot-yet-suppressed under PD-1 blockade: an RMP-NRF2-PD-L1 axis associated with a reduced proportional response in hepatocellular carcinoma.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Immune checkpoint blockade (ICB) provides therapeutic benefits to a subset of patients with hepatocellular carcinoma (HCC); however, reliable predictors of treatment efficacy remain scarce. This study investigates whether RPB5-mediating protein (RMP) facilitates the alignment of redox adaptation with immune checkpoint regulation, thereby influencing the extent of therapeutic benefit under programmed cell death protein 1 (PD-1) blockade. In Hepa1-6 and Hep3B cell lines, enforced expression of RMP resulted in elevated levels of NRF2 and PD-L1 proteins, alongside enhanced clonogenic growth and short-term migratory capacity. In a subcutaneous Hepa1-6 tumor model, RMP-overexpressing tumors exhibited accelerated growth and a distinct immunohistochemical profile characterized by increased levels of RMP, NRF2, PD-L1, Ki-67 and HO-1, indicative of a proliferative and redox-adapted state. Upon administration of anti-PD-1 therapy, both experimental cohorts demonstrated tumor regression; however, the RMP-overexpressing cohort exhibited a proportionally reduced inhibition compared to controls, despite experiencing greater absolute tumor shrinkage from a higher baseline. This suggests a limited response amplitude within the RMP/NRF2-high context. Post-therapy tissues from the overexpression cohort exhibited elevated levels of RMP, NRF2, HO-1, and PD-L1, alongside an immune microenvironment characterized by an increased presence of CD3/CD8 cells and a decreased presence of CD4/CD25 cells. This pattern is indicative of an inflamed yet suppressed state of adaptive immune resistance. Collectively, these observations support a model wherein continuous RMP-NRF2-HO-1 activity and persistent PD-L1 expression exert inhibitory pressure, even as PD-1 blockade facilitates cytotoxic T-cell infiltration. This dynamic accounts for the relatively lower inhibition observed in the overexpression context. The combined RMP/NRF2/PD-L1 signature proposes a mechanistically informed biomarker framework and suggests the potential for rational therapeutic combinations that pair PD-1 blockade with modulation of the redox pathway in HCC.
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