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Immunol."],"abstract":"<jats:p>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\u20136 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\u20136 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\u2013NRF2\u2013HO-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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1737569","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T06:45:12Z","timestamp":1770273912000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hot\u2212yet\u2212suppressed under PD\u22121 blockade: an RMP\u2013NRF2\u2013PD\u2212L1 axis associated with a reduced proportional response in hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Mingzhu","family":"Zuo","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"School of Pharmacy, Xi\u2019an Jiaotong 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