Radiofrequency ablation (RFA) can destroy hepatocellular carcinoma (HCC) through the thermal-killing effect and increase tumor immunogenicity by releasing tumor cell debris. However, insufficient RFA (iRFA) is frequently encountered and leaves behind malignant tissues in clinical settings. The immune responses induced by RFA are too weak to trigger an efficient immune response to eliminate residual tumors. Toll-like receptor (TLR) 7/8 agonists serve as potent immunological adjuvants in combinatorial cancer immunotherapy, capable of enhancing RFA-mediated immune responses. Nevertheless, the poor bioavailability and off-target toxicities compromised their clinical applications. To address this clinical challenge, mechanistic investigations is initially conducted and revealed that iRFA exacerbates tumor hypoxia and induces immune suppression. Building on these findings, azobenzene (Azo) is strategically utilized as a cleavable linker to prepare a novel hypoxia-activated TLR 7/8 agonist imidazoquinoline (IMDQ) prodrug nanoparticles (Azo-IMDQ-NPs) to enhance RFA-mediated antitumor immunity. Azo-IMDQ-NPs can be selectively reduced to IMDQ in aggravated hypoxic tumor microenvironments (TME) induced by iRFA, thereby reprogramming immunosuppressive TME, triggering potent antitumor immune responses to eliminate residual tumors, and establishing a long-term immunological memory effect to prevent tumor recurrence. This study proposed a novel strategy for engineering hypoxia-activated prodrug nanoparticles to potentiate RFA-mediated antitumor immunity against HCC and further extend its clinical value.