{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T13:07:07Z","timestamp":1784207227100,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The perioperative period is increasingly recognized as a biologically active interval in which surgical injury, anesthetic exposure, neuroendocrine stress, pain, opioid use, and innate immune remodeling may influence residual tumor-cell ecology. Postoperative nausea and vomiting (PONV) provides a clinically validated perioperative phenotype of substance P (SP)\/neurokinin-1 receptor (NK1R; TACR1) pharmacology, because NK1R antagonists are established antiemetic agents for selected high-risk patients. The relevance of this pharmacology to cancer does not rest on a shared PONV-tumor mechanism; rather, it rests on the fact that the same druggable receptor can be targeted within familiar perioperative dosing windows. PONV is therefore used here as a clinical pharmacology entry point to consider whether perioperative SP\/NK1R signaling may have additional relevance as a candidate neuro-innate immune circuit within the tumor microenvironment. Recent evidence supports biological plausibility, but the mechanistic core remains narrow. Sensory-neuron-derived SP can activate tumoral TACR1 and extracellular RNA\/TLR7-dependent metastatic programs in breast cancer models. A separate cancer-induced nerve-injury model supports the broader concept that neural injury can affect checkpoint responsiveness, but its IL-6\/type 1 interferon\/ATF-3 mechanism is distinct from SP\/NK1R signaling. These findings fit a broader cancer-neuroscience framework in which tumor-associated nerves, neuropeptides, macrophages, neutrophil extracellular traps, extracellular RNA sensing, and inflammatory myeloid states may interact during perioperative stress. These contextual observations should not be read as direct SP\/NK1R-specific evidence. Nevertheless, antiemetic efficacy should not be equated with proven anticancer efficacy. Available evidence remains dominated by a single causal breast cancer model, tumor expression studies, and emerging clinical associations; prospective perioperative trials have not established that NK1R blockade reduces recurrence, metastasis, or immunotherapy resistance. The next step should be biomarker-embedded perioperative research integrating PONV phenotyping, circulating SP, TACR1 expression, neutrophil extracellular trap markers, monocyte activation, extracellular RNA\/TLR signatures, spatial tumor innervation, minimal residual disease readouts, and long-term oncologic outcomes. SP\/NK1R signaling should therefore be viewed as a plausible and clinically tractable perioperative translational hypothesis, not yet as a validated oncologic intervention.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1896684","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:07:35Z","timestamp":1784203655000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Perioperative substance P\/NK1R pharmacology: from PONV control to a testable cancer neuro-immune hypothesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shaanxi Provincial Cancer Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000004833","article-title":"Fourth consensus guidelines for the management of postoperative nausea and vomiting","volume":"131","author":"Gan","year":"2020","journal-title":"Anesth Analg"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.194","article-title":"Perioperative events influence cancer recurrence risk after surgery","volume":"15","author":"Hiller","year":"2018","journal-title":"Nat Rev Clin 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