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Abstract
Chemotherapy, which primarily acts on cancer cells, can influence the tumor microenvironment and the recruitment and behavior of stromal cells. In this issue of the JCI, Li et al. explored the potent anticancer effect of the combination of a glutaminase inhibitor (CB-839) and 5-FU against PIK3CA-mutant colorectal cancer tumors. This chemotherapy treatment strongly induced the recruitment of neutrophils that formed neutrophil extracellular traps in cancer, which actively killed cancer cells by inducing apoptosis. This study substantially advances our understanding of the multifaceted role of neutrophils and NETs in the outcome of anticancer treatment.
Authors
Alexandra Mousset, Jean Albrengues
Figure 1
NETs induced by chemotherapy inhibit CRC tumor growth.
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Li and colleagues (4 ) present a mechanism by which NETs formed in response to chemotherapy induce PIKCA-mutant CRC cell apoptosis. Combination treatment of a CB839 and 5-FU upregulates IL-8 secretion by cancer cells, resulting in neutrophil recruitment in tumors. In addition, the CB-839/5-FU combination treatment induces ROS accumulation in neutrophils, which results in NET formation. NETs contain CG, which can enter in cancer cells via the cell surface protein RAGE. Once internalized, CG cleaves 14-3-3ε, which induces BAX mitochondrial translocation, triggers apoptosis, and results in tumor regression.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)