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REVIEW

Next Generation DNA Damage Response Inhibitors: Harnessing Nanocarriers and Tumor Microenvironment for Precision Cancer Therapy

Abhishikt David Solomon1,*, Himanshu Kumar Vats2,#, Shivam Chowdhary3,#, Supriya Nandlal Kanoujiya4, Ajit Prakash5, Hina Sultana6, Sabyasachi Mohanty7, Billy W. Day8, Tarun Pant9,10,*
1 Division of Oral and Craniofacial Health Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2 Department of Molecular and Cellular Engineering, Jacob Institute of Biotechnology and Bioengineering, Prayagraj, 211007, India
3 Manipal Institute of Virology, Manipal Academy of Higher Education, Manipal, 576104, India
4 School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India
5 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
6 Integrative Program for Biological and Genome Sciences (iBGS), UNC Chapel Hill, Chapel Hill, NC 27599, USA
7 Department of Chemical and Bio-Molecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
8 ReNeuroGen LLC, Milwaukee, WI 53122, USA
9 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
10 Children’s Research Institute, Children’s Wisconsin, Milwaukee, WI 53226, USA
* Corresponding Author: Abhishikt David Solomon. Email: email; Tarun Pant. Email: email
# Both authors contributed equally

Oncology Research https://doi.org/10.32604/or.2026.071632

Received 09 August 2025; Accepted 05 January 2026; Published online 28 January 2026

Abstract

Tumor survival, genomic stability, and therapy resistance are dictated by the DNA damage response (DDR). Although poly (ADP-ribose) polymerase (PARP) inhibitors have established the DDR as a therapeutic target, many tumors evade first-generation drugs by rewiring their adaptive repair pathways and imposing microenvironmental constraints. This review synthesizes recent discoveries in key DDR pathways, such as PARP, ataxia telangiectasia and Rad3-related kinase (ATR), ataxia telangiectasia mutated kinase (ATM), checkpoint kinase 1 (CHK1), WEE1 G2 checkpoint kinase (WEE1), and DNA-dependent protein kinase (DNA-PK), and describes the next-generation inhibitors designed to increase selectivity and circumvent resistance. We also analyze the role of hypoxia, stromal remodeling, inflammatory cytokines, and immune-cell plasticity in the tumor microenvironment in determining DDR dependency and response. Special attention is paid to cGAS-STING, immunogenic signaling via damage-associated molecular patterns (DAMPs), and mechanisms that convert a cold tumor into a hot one. Lastly, we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics, target resistant tumor niches, and expand the possibilities for combinatorics with immunotherapy and radiotherapy. Collectively, these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate, durable, and context-specific cancer therapy.

Keywords

DNA damage response (DDR); DDR inhibitors (DDRis); tumor microenvironment

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