{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:42:30Z","timestamp":1793727750500,"version":"4.6.1"},"reference-count":43,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"unspecified","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the Leading Earth Goose Program of Zhejiang Province, China","award":["No.2025C02132"],"award-info":[{"award-number":["No.2025C02132"]}]},{"name":"the Pioneer Program of Zhejiang Province, China","award":["No.2025C01114"],"award-info":[{"award-number":["No.2025C01114"]}]},{"name":"the CAMS Innovation Fund for Medical Sciences","award":["CIFMS, 2019-I2M-5-044"],"award-info":[{"award-number":["CIFMS, 2019-I2M-5-044"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,24]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Local tumor progression and metastasis substantially compromise the therapeutic efficacy of thermal ablation in liver cancer. Although the inflammatory microenvironment contributes, the specific role of neutrophils after ablation remains unclear. This study aimed to clarify the roles of neutrophil extracellular traps (NETs) after thermal ablation and evaluate the translational potential of NETs-targeted strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The adverse prognostic impact of thermal ablation-induced neutrophil and inflammatory changes in liver cancer was retrospectively evaluated. Circulating NETs were quantified by ELISA, and their association with local tumor progression was analyzed. An orthotopic liver cancer mouse model and patient-derived neutrophils elucidated the spatiotemporal dynamics and mechanisms of ablation-induced NETs, and pharmacologic inhibition was used to investigate NET formation, function, and translational potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Thermal ablation rapidly activates neutrophils, elicits a sustained local inflammatory response and NET formation, which is closely associated with poor prognosis in patients with liver cancer. Depletion of neutrophils, inhibition of NET formation, or degradation of thermal ablation-induced NETs markedly suppressed post-ablation tumor progression. Mechanistically, tumor cell-intrinsic reactive oxygen species generated under heat stress contributed to nuclear factor kappa-B (NF-\u03baB) activation, promoting p65 binding to theC-X-C motif chemokine ligand 1 (CXCL1) promoter and transcriptional upregulation of CXCL1. This process drove CXCL1-C-X-C motif chemokine receptor 2 (CXCR2) signaling and led to the formation of a characteristic band-like NETs-enriched zone at the peri-ablational margin. In turn, NETs activated toll-like receptor (TLR)9-dependent NF-\u03baB,mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3) signaling in heat-stressed cancer cells, reinforcing a pro-inflammatory feedback loop. Concurrently, NETs impaired CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses and fostered an immunosuppressive microenvironment. Together, this coordinated pro-inflammatory and immunosuppressive effect promotes liver cancer progression following thermal ablation, which can be effectively reversed by dual blockade of NF-\u03baB and CXCR2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our research uncovers a novel mechanism underlying tumor-promoting inflammation after thermal ablation, highlighting the critical role of NETs as mediators through TLR9 activation of downstream inflammatory pathways and the significant potential of NETs-targeted strategies in combination with thermal ablation.<\/jats:p>\n                  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