Figure

Clear cell renal cell carcinoma (ccRCC) exhibits paradoxical immune characteristics, with abundant CD8⁺ T cell infiltration failing to translate into favorable clinical outcomes. The mechanisms underlying this immune resistance remain poorly defined. Here, we identify TRIM28 as a central mediator of immune evasion in ccRCC through integrated computational screening and functional validation. Using a high-throughput gene knockout simulation based on Geneformer, we pinpointed TRIM28 as a key regulator of tumor-intrinsic immune suppression. TRIM28 depletion reprograms malignant epithelial cells toward a less aggressive state and enhances tumor cell susceptibility to CD8⁺ cytotoxic T lymphocyte (CTL)-mediated killing. Mechanistically, TRIM28 stabilizes PARP1 protein via SUMO2 conjugation, thereby reducing nuclear NAD⁺ availability and suppressing SIRT1 activity. This results in increased acetylation of NF-κB p65 and upregulation of PD-L1 expression. In parallel, TRIM28-driven NAD⁺ consumption in tumor cells limits NAD⁺ level for neighboring CD8⁺ T cells, impairing their metabolic fitness and effector function. Structure-based screening identifies erlotibop as a TRIM28 inhibitor, which synergizes with PD-1 blockade to extend survival. This dual mechanism integrates immunoregulatory and metabolic pathways, offering a comprehensive explanation for the “immune-inflamed but unresponsive” phenotype observed in ccRCC. Collectively, our findings position TRIM28 as a critical immunometabolic checkpoint and highlight its potential as a therapeutic target for overcoming immune resistance in ccRCC.