A Multifunctional Prodrug with the DNA Damage Amplification Effect for Inducing Immunogenic Cell Death

  • J Med Chem. 2026 Jan 22;69(2):1286-1302. doi: 10.1021/acs.jmedchem.5c02668.
Haolin Zhang  1  2 ,  Guisen Li  1  2 ,  Chunling Chen  1  2 ,  Jiayu Ding  1  2 ,  Hao Shen  1  2 ,  Wenjian Min  1  2 ,  Peng Yang  1  2  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and Innovative Drugs, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41481577 DOI: 10.1021/acs.jmedchem.5c02668
Abstract

While immunogenic cell death (ICD) represents an effective approach to augment traditional immunotherapy, the clinical utility of ICD inducers is constrained by their potency and toxicity profiles. In this study, we engineered a novel functional prodrug, Ola-NC-SS-PEG-Lap, which exploits the synergistic interplay between an NQO1-bioactivated compound and a PARP Inhibitor to selectively induce ICD in tumor cells without harming normal cells. Compared to monotherapies or their coadministration, Ola-NC-SS-PEG-Lap elicited superior Reactive Oxygen Species (ROS) production, leading to increased DNA damage. This damage was further potentiated by the inhibition of PARP-mediated DNA repair, resulting in robust ICD induction in vitro. Furthermore, in an MC38 syngeneic mouse model, Ola-NC-SS-PEG-Lap significantly suppressed tumor growth in the absence of observable toxicity or weight loss. The treatment also delayed tumorigenesis by reprogramming the immunosuppressive tumor microenvironment and generating lasting antitumor immune memory.

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