High-risk patients (enriched with Tregs/MDSCs) show primary resistance to ICIs due to: (1) upregulated checkpoint molecules (e.g., TIM-3, LAG-3) beyond PD-1 [37]; (2) exclusion of CD8 + T cells from tumor nests [49] Conversely, low-risk patients—with favorable immune infiltration (e.g., cytotoxic CD8 + T cells)—respond better to PD-1 blockade [39]. The gene discussed is CD8A; the disease is neoplasm.