Extracellular DNA (exDNA) (exDNA)

Extracellular DNA (exDNA), also referred to as cell-free DNA (cfDNA), consists of nucleic acid fragments released into the extracellular environment and systemic circulation primarily through cell death processes such as necrosis and apoptosis [8, 19]. In the context of oncology, necrotic tumor cells release significant quantities of both single- and double-stranded DNA, which often remains associated with histones to form stable DNA-histone complexes in the necrotic core [7, 9]. This extracellular DNA acts as a potent damage-associated molecular pattern (DAMP), triggering innate immune sensors such as Toll-like receptor 9 (TLR9) and the cGAS-STING pathway, which can drive chronic inflammation and promote a pro-metastatic microenvironment [2, 12]. Therapeutically, this entity is exploited as a target for Tumor Necrosis Therapy (TNT), where monoclonal antibodies like NHS76 bind specifically to exposed DNA in necrotic regions to deliver therapeutic agents, such as interleukin-12 (NHS-IL12) or radioactive isotopes (131I-chTNT-1/B) [6, 7, 9]. Additionally, enzymes like DNase I are being explored to degrade these DNA structures to disrupt the tumor-supporting matrix and inhibit metastatic spread [2, 5]. The presence and integrity of this DNA in the blood also serve as critical biomarkers for cancer diagnosis and monitoring [8, 19].

Other names

Cell-free DNA (cfDNA)Circulating tumor DNA (ctDNA)DNA-histone complexNecrotic DNAExtracellular single- and double-stranded DNA

Tumor necrosis targeting to deliver immunomodulatory or cytotoxic payloads; enzymatic degradation of extracellular DNA to disrupt the pro-metastatic microenvironment.