TRIM28 drives immune evasion via PARP1 SUMOylation and NAD + depletion in clear cell renal cell carcinoma

BACKGROUND: T cells does not necessarily correlate with improved prognosis, indicating the presence of unique immune evasion mechanisms within the tumor microenvironment (TME). METHODS: T cell co-cultures, flow cytometry, and patient-derived xenograft models. Co-immunoprecipitation and GST pull-down assays were used to analyze the TRIM28-poly (ADP-ribose) polymerase 1 (PARP1) interaction. SUMOylation/ubiquitination studies elucidated the mechanism regulating PARP1 stability, and chromatin immunoprecipitation-quantitative PCR identified the transcriptional regulation of programmed death-ligand 1 (PD-L1). High-throughput screening was conducted with RNA-seq, liquid chromatography-tandem mass spectrometry, and metabolomics. Virtual screening identified the TRIM28 inhibitor Eltrombopag, which was tested in combination with anti-programmed cell death protein-1 (PD-1) therapy for in vivo efficacy and metabolic reprogramming. RESULTS: T cell dysfunction. Notably, we identified Eltrombopag as a candidate TRIM28 inhibitor, which synergized with anti-PD-1 therapy to enhance antitumor immunity and overcome ICB resistance in murine models. CONCLUSIONS: metabolic reprogramming. Targeting TRIM28/PARP1/PDL1 with Eltrombopag reshapes the immunosuppressive TME and enhances checkpoint blockade efficacy, providing a novel combinatorial strategy for ccRCC immunotherapy.