ChemoNETosis in Cancer: A Comprehensive Review of Treatment-Induced NET Formation and Therapeutic Consequences

TL;DR

ChemoNETosis is a chemotherapy-induced immune response that promotes tumor resistance and could be targeted to improve cancer treatment outcomes.

Contribution

This is the first comprehensive review of chemoNETosis, detailing its mechanisms and therapeutic implications across solid tumors.

Findings

ChemoNETosis involves chemotherapy-induced neutrophil extracellular trap (NET) formation in tumors and metastases.

NETs contribute to chemoresistance by activating TGFβ and promoting tumor cell plasticity.

NET biomarkers like CitH3 and cfDNA may help identify patients who could benefit from NET-targeted therapies.

Abstract

What are the main findings?
ChemoNETosis represents a treatment-induced neutrophil extracellular trap (NET) program in which cytotoxic chemotherapy alters the cytokine and chemokine landscape of the tumor microenvironment, including signals such as interleukin 1 beta (IL 1β) and the C X C motif chemokine ligand 1 and 5–C X C chemokine receptor 2 (CXCL1 and CXCL5–CXCR2) axis. These changes facilitate neutrophil recruitment and activation, culminating in NET deposition within primary tumors and metastatic niches.NET-enriched microenvironments can contribute mechanistically to chemoresistance by promoting epithelial to mesenchymal transition and tumor cell plasticity, for example through NET scaffold-associated activation of latent transforming growth factor beta (TGF β) signaling. In selected clinical contexts, this process may also connect therapy-induced inflammatory stress with vascular dysfunction and systemic toxicities.

ChemoNETosis represents a treatment-induced neutrophil extracellular trap (NET) program in which cytotoxic chemotherapy alters the cytokine and chemokine landscape of the tumor microenvironment, including signals such as interleukin 1 beta (IL 1β) and the C X C motif chemokine ligand 1 and 5–C X C chemokine receptor 2 (CXCL1 and CXCL5–CXCR2) axis. These changes facilitate neutrophil recruitment and activation, culminating in NET deposition within primary tumors and metastatic niches.

NET-enriched microenvironments can contribute mechanistically to chemoresistance by promoting epithelial to mesenchymal transition and tumor cell plasticity, for example through NET scaffold-associated activation of latent transforming growth factor beta (TGF β) signaling. In selected clinical contexts, this process may also connect therapy-induced inflammatory stress with vascular dysfunction and systemic toxicities.

What are the implications of the main findings?
ChemoNETosis identifies therapeutically actionable checkpoints that may be incorporated into rational combination strategies. These include enzymatic NET disruption using deoxyribonuclease (DNase), inhibition of peptidylarginine deiminase 4 (PAD4) to prevent chromatin decondensation, and targeting upstream inflammatory circuits such as IL 1β or CXCR2 signaling, with the aim of restoring chemotherapy and potentially immunotherapy sensitivity without broadly compromising host defense.Circulating and tissue-based NET biomarkers, including citrullinated histone H3 (CitH3), neutrophil elastase–DNA (NE–DNA) complexes, and cell-free DNA (cfDNA), may assist in patient stratification and treatment monitoring, and could help identify resistance phenotypes in which NET-directed adjunctive strategies are most likely to provide clinical benefit.

ChemoNETosis identifies therapeutically actionable checkpoints that may be incorporated into rational combination strategies. These include enzymatic NET disruption using deoxyribonuclease (DNase), inhibition of peptidylarginine deiminase 4 (PAD4) to prevent chromatin decondensation, and targeting upstream inflammatory circuits such as IL 1β or CXCR2 signaling, with the aim of restoring chemotherapy and potentially immunotherapy sensitivity without broadly compromising host defense.

Circulating and tissue-based NET biomarkers, including citrullinated histone H3 (CitH3), neutrophil elastase–DNA (NE–DNA) complexes, and cell-free DNA (cfDNA), may assist in patient stratification and treatment monitoring, and could help identify resistance phenotypes in which NET-directed adjunctive strategies are most likely to provide clinical benefit.

ChemoNETosis represents a distinct form of therapy-induced innate immune activation, in which cytotoxic chemotherapy alters the tumor microenvironment (TME) in ways that attract and stimulate neutrophils, ultimately triggering the release of neutrophil extracellular traps (NETs). Unlike classical NETosis, which typically arises in response to infection or sterile inflammation, chemoNETosis is initiated by treatment-related danger signals and chemokine–cytokine loops that reshape the immune landscape and promote the formation of NET-rich metastatic niches. These NET structures serve not only as physical scaffolds but also as bioactive platforms enriched with proteases, reactive oxygen species, and enzymes capable of activating growth factors, collectively driving epithelial–mesenchymal transition, enhanced tumor cell plasticity, immune cell exclusion, changes in vascular permeability, and the development of chemotherapy resistance. While predominantly associated with tumor-promoting effects, chemoNETosis may, under specific genetic or metabolic conditions, contribute to antitumor responses, reflecting its context-dependent plasticity. In this review, we present what is, to our knowledge, the first in-depth synthesis of chemoNETosis across solid tumors, with a focus on key mechanistic nodes and translational perspectives.

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