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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\u2010like receptor (TLR) 7\/8 agonists serve as potent immunological adjuvants in combinatorial cancer immunotherapy, capable of enhancing RFA\u2010mediated immune responses. Nevertheless, the poor bioavailability and off\u2010target 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\u2010activated TLR 7\/8 agonist imidazoquinoline (IMDQ) prodrug nanoparticles (Azo\u2010IMDQ\u2010NPs) to enhance RFA\u2010mediated antitumor immunity. Azo\u2010IMDQ\u2010NPs 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\u2010term immunological memory effect to prevent tumor recurrence. This study proposed a novel strategy for engineering hypoxia\u2010activated prodrug nanoparticles to potentiate RFA\u2010mediated antitumor immunity against HCC and further extend its clinical value.<\/jats:p>","DOI":"10.1002\/smll.202505833","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T15:56:02Z","timestamp":1761148562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hypoxia\u2010Activated Imidazoquinoline Prodrug Nanoparticles Potentiate Radiofrequency Ablation\u2010Mediated Antitumor Immunity Against Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0664-656X","authenticated-orcid":false,"given":"Guofeng","family":"Ji","sequence":"first","affiliation":[{"name":"Department of General Surgery Xuanwu Hospital Capital Medical University  Beijing 100053 P. R. 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