CircSPECC1 attenuates sensitivity to PD-1 blockade through impaired antigen presentation in hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) demonstrate therapeutic benefits in advanced hepatocellular carcinoma (HCC), yet most patients exhibit limited responses to anti-PD-1 therapy and the molecular basis underlying this resistance remains largely undefined. Here, we identified the circular RNA SPECC1 (circSPECC1) as a regulator of antigen presentation and a crucial factor influencing the efficacy of anti-PD-1 therapy. circSPECC1 was significantly elevated in tumor tissues of HCC patients showing resistance to anti-PD-1 therapy and correlated with diminished intratumoral CD8+ T-cell infiltration. Elevated circSPECC1 levels facilitated tumor progression and impaired the therapeutic efficacy of anti-PD-1 treatment. Overexpression of circSPECC1 in cancer cells suppressed the proliferation and cytotoxic activity of CD8+ T cells both in vitro and in vivo. Mechanistically, circSPECC1 bound to the peptide-loading complex (PLC) chaperone ERP57 and disrupted its interaction with TAPBP (TAP binding Protein), thereby destabilizing PLC integrity. This aberrant interaction redirected MHC-I toward ER-associated degradation (ERAD), suppressing surface antigen presentation and impairing CD8+ T-cell activation. Importantly, targeted silencing of circSPECC1 using a PEG-PEI-folate nanosystem encapsulating si-circSPECC1 significantly restored sensitivity both murine and patient-derived xenograft HCC models to PD-1 blockade. In summary, these findings uncover a novel circRNA-guided ERAD of MHC-I mechanism that impairs antitumor immunity and highlight circSPECC1 as a promising therapeutic target to overcome immunotherapy resistance.