RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress

Objective: To investigate the role and molecular mechanism of the E3 ubiquitin Ligase RNF26 in regulating the immunogenicity of hepatocellular carcinoma (HCC).

Methods: We integrated multi-omics analyses of clinical HCC specimens with different immunogenicity, established HCC models using hepatocyte-specific Rnf26 knockout mice, and employed in vitro 3D tumor-T cell co-culture systems, RNA-seq, molecular interaction assays, and pharmacological inhibition to systematically examine RNF26's regulation of T cell function, antigen presentation, and endoplasmic reticulum (ER) stress.

Results: RNF26 was highly expressed in immune-"cold" HCC, and its transcription was directly regulated by the inflammatory JAK-STAT3 axis. In HCC cells, RNF26 degraded the ER chaperone GRP78 via K48-linked polyubiquitination, inducing sustained ER stress. This resulted in diminished MHC-I antigen presentation and increased PD-L1 expression. This mechanism consistently inhibited CD8⁺ T cell infiltration, promoted T cell exhaustion, and drove immune evasion in both in vivo and in vitro models. Inhibiting ER stress reversed the RNF26-mediated immunosuppressive phenotype.

Conclusion: RNF26 is a pivotal molecular node linking the inflammatory microenvironment to immune suppression in HCC. By ubiquitinating and degrading GRP78 to instigate ER stress, it dually regulates antigen presentation and immune checkpoint expression. Targeting the RNF26-GRP78 axis represents a promising novel strategy for reversing HCC immune resistance and enhancing the efficacy of immunotherapy.

ER stress; Hepatocellular Carcinoma (HCC); Immune resistance; Major histocompatibility complex-1; PD-L1; RNF26.