Integrative Genomic and Single-Cell Insights Into Efferocytosis-Mediated Immune Regulation in Clear Cell Renal Cell Carcinoma.

Background: Efferocytosis, the phagocytic clearance of apoptotic cells, plays a key role in tumor progression and immune regulation, but its prognostic significance and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. Methods: Four efferocytosis-related pathways were curated, and the pathway activities were quantified in ccRCC. Prognostic genes were identified by univariate Cox regression and used to construct linear survival models with multiple algorithms, with the optimal model selected by cross-validation. Associations between the risk score and tumor mutational burden (TMB), mutation profiles, and copy number variation (CNV) were subsequently evaluated. Multiomics integration highlighted RAC1 as a key risk gene, which was further examined using single-cell and spatial transcriptomics (ST) to characterize expression patterns, tumor microenvironment interactions, and pathway enrichments. Protein-level validation was performed using immunohistochemistry (IHC) data from the Human Protein Atlas. Results: Efferocytosis pathway activity was upregulated in ccRCC, increased with disease stage, and correlated with poorer survival. The ridge regression-based prognostic model demonstrated consistent predictive performance across independent datasets and was associated with higher TMB, specific mutation patterns, and increased CNV. Notably, RAC1, identified as the top weighted gene in the model, was overexpressed in association with copy number amplification, showing preferential enrichment in malignant core regions and strong links to oncogenic signaling. Conclusion: Efferocytosis activation characterizes aggressive ccRCC. The developed prognostic model and identification of RAC1 as a central effector link efferocytosis-related risk to immune remodeling and oncogenic signaling, providing potential biomarkers and therapeutic targets.