Discovery of FAP-Targeted Platinum(IV)-Esterified STING Agonist as Small-Molecule Dual Prodrug Conjugates for...

Tumor-specific activation of the stimulator of the interferon genes (STING) pathway is essential for maximizing antitumor efficacy while minimizing systemic toxicity of STING agonists. Conjugating STING agonists with tumor-targeting warheads has emerged as a promising strategy in cancer immunotherapy. In this study, we designed and synthesized a series of fibroblast activation protein (FAP)-targeting platinum (Pt)-(IV)-centered STING agonist conjugates by esterifying the two axial hydroxyls of Pt-(IV) species with STING agonist MSA-2 and the FAP warhead, respectively. Among the synthesized conjugates, 21b exhibited picomolar binding affinity to FAP and preferentially accumulated in 3T3-hFAP cells. Under hypoxic tumor conditions, these conjugates release the active Pt-(II) species to induce tumor cell death and simultaneously liberate MSA-2 to activate the STING/IFN-mediated antitumor immune response. In colon tumor-bearing mice, 21b mainly distributed in tumor tissue and showed significantly enhanced antitumor activity and reduced toxicity. Compared to MSA-2 alone, it promoted more CD8⁺ T-cell infiltration and reduced FAP⁺ cell populations in tumors. Importantly, it selectively elevated TNF-α and IP-10 levels in tumor tissue without increasing serum cytokine levels, indicating tumor-specific STING pathway activation. These findings provide strong proof of concept for FAP-targeted Pt-(IV)-STING agonist conjugates as a novel tumor-specific metalloimmunotherapy.