Abstract

In this Perspective, we present a non-systematic narrative synthesis and propose a hypothesis-generating framework that links regional anesthesia, local anesthetic strategies, surgery-induced NETosis, and perioperative metastatic biology. Surgical tumor resection coincides with a biologically vulnerable perioperative period characterized by inflammatory activation, innate immune remodeling, and potential metastatic susceptibility. Preclinical evidence suggests that this interval may represent a transient metastatic window in which circulating tumor cells and host inflammatory responses overlap, potentially favoring metastatic implantation. Among the mechanisms implicated in this process, neutrophil extracellular traps (NETs) have been implicated in tumor-cell capture, endothelial interaction, immune evasion, and metastatic outgrowth. Experimental studies further suggest that surgery-induced NETosis may contribute to prometastatic signaling and tumor-cell metabolic adaptation during the postoperative period. Human evidence remains more limited and heterogeneous. Observational studies indicate that NET-related biology is active during oncologic surgery, with the presence of tissue NETs and circulating NET-associated biomarkers correlating with tumor stage, inflammatory context, or tumor burden in selected malignancies. Perioperative clinical studies also suggest that regional anesthesia and local anesthetic-based strategies, including intravenous lidocaine, may influence neutrophil activation and postoperative NET-associated biomarkers. However, robust evidence of clinical oncologic outcomes remains limited, and a clear distinction between surrogate perioperative endpoints and long-term clinical outcomes is still lacking. Within this context, we propose that regional anesthesia may influence pathways associated with perioperative tumor–host interactions not primarily through opioid sparing but through modulation of mechanisms related to surgery-induced NETosis during a short-lived biological window. The neutral results of large survival-based trials do not necessarily invalidate this hypothesis; rather, they underscore the limitations of conventional oncologic endpoints in capturing transient perioperative biological effects. This Perspective outlines a translational research agenda centered on biomarker-driven perioperative studies integrating NET-specific markers, circulating tumor cell dynamics, and temporally precise postoperative sampling.

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