Perioperative substance P/NK1R pharmacology: from PONV control to a testable cancer neuro-immune hypothesis

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.