Our investigations demonstrate that this approach simultaneously inhibited PD-L1-mediated immunosuppressive signaling and silenced CD47 expression, thereby suppressing tumor growth, induces selective depletion and metabolic alteration of Tregs, and boosts CD8+ T cell infiltration, establishing aptamer-siRNA conjugates as a platform for effective RNAi-based immunomodulation within the TME. The gene discussed is CD8A; the disease is neoplasm.