Surgery May Open a Window for Cancer Spread, and Anesthesia Could Help Close It

Surgery remains the cornerstone of curative cancer treatment, yet a growing body of research suggests that the operation itself may briefly tip the balance in favor of any tumor cells left behind. A comprehensive new review published in Holistic Integrative Oncology synthesizes the mechanistic evidence behind this paradox, describing a stress–inflammation–immunosuppression axis that surgery ignites and that anesthesia may help to moderate. The authors, led by Liu Ye and Linghui Pan of Guangxi Medical University Cancer Hospital, argue that the perioperative period is not simply a technical interlude between diagnosis and adjuvant therapy, but a biologically consequential window during which residual cancer cells are most vulnerable to immunological attack and, simultaneously, most able to exploit a temporarily hostile immune environment.

At the center of the review is the observation that surgical trauma activates two major neuroendocrine systems. The hypothalamic–pituitary–adrenal axis floods the circulation with glucocorticoids, which suppress the synthesis of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha through their effects on transcription factors like nuclear factor kappa B, while also impairing antigen presentation and lymphocyte proliferation. In parallel, the sympathetic nervous system releases catecholamines that bind beta-adrenergic receptors expressed on tumor cells, endothelial cells and immune populations. These signals promote epithelial-mesenchymal transition, angiogenesis and metastatic dissemination, and they reshape immunity by suppressing natural killer cell cytotoxicity, expanding myeloid-derived suppressor cells and regulatory T cells, and even upregulating the CD47/SIRPalpha “don’t eat me” pathway that shields tumor cells from macrophage phagocytosis. With an estimated ninety percent of cancer-related deaths attributable to metastatic disease after tumor resection, the authors contend that this axis deserves far more clinical attention than it currently receives.

The inflammatory arm of the axis is equally intricate. Surgery triggers a cytokine surge dominated by IL-6 and TNF-alpha, which activate the JAK/STAT3 and NF-kappaB pathways respectively, driving tumor cell proliferation, survival and immune evasion. These cytokines can also endow tumor cells with cancer stem cell-like properties, enhancing resistance to chemotherapy and radiotherapy, and they bias tumor-associated macrophages toward a pro-tumor M2 phenotype that fosters angiogenesis and metastasis. The review also highlights neutrophil extracellular traps, or NETs, web-like structures of DNA, histones and neutrophil proteins released in response to inflammatory stimuli such as IL-8, TNF-alpha and damage-associated molecular patterns. NETs can capture circulating tumor cells, promote their adhesion and colonization at distant sites, and suppress NK and cytotoxic T cell activity. In metastatic hepatocellular carcinoma models, NET internalization activates TLR4/9-COX2 signaling in a feed-forward loop that amplifies both NET formation and metastatic potential, while DNase I combined with anti-inflammatory agents reduced metastasis in mouse models.

The review then details how surgery expands immunosuppressive cell populations. Myeloid-derived suppressor cells accumulate from the bone marrow under the influence of tumor-derived factors, including exosomal PD-L1 that stimulates MDSC proliferation via IL-6/STAT3 signaling. Once activated, MDSCs deplete L-arginine through arginase 1 and inducible nitric oxide synthase, reducing CD3-zeta expression and interferon-gamma and IL-2 secretion, while granulocytic MDSCs nitrate the T-cell receptor through reactive oxygen species. MDSCs also inhibit NK cell cytotoxicity in a cell contact-dependent manner reliant on the NKp30 receptor. In patients undergoing cancer surgery, this expansion has been linked to impaired Th1 immune function, higher postoperative infection risk and increased tumor recurrence. Regulatory T cells follow a parallel trajectory: peripheral Treg levels rise significantly one week after radical mastectomy, accompanied by enhanced inhibitory activity and upregulated checkpoint molecules such as CTLA-4 and PD-1, and propranolol can abolish this catecholamine-driven increase.

Against this mechanistic backdrop, the review systematically appraises anesthetic agents, and the picture that emerges is deliberately nuanced. Propofol emerges as the most frequently discussed “immune-friendly” option. It inhibits cyclooxygenase activity in monocytes and macrophages, lowering prostaglandin E2 production and thereby relieving constraints on NK cell interferon-gamma output. Preclinical work shows it does not reduce NK activity or increase metastatic seeding compared with ketamine, thiopental or halothane, and it suppresses hypoxia-inducible factor-1alpha and RhoA-linked invasion pathways. Clinical studies report more favorable postoperative NK-cell cytotoxicity and reduced VEGF-C release with propofol-based regimens, though a large multicenter randomized trial found no breast cancer recurrence benefit from paravertebral block plus propofol compared with sevoflurane plus opioids. Direct evidence that propofol independently improves long-term oncologic outcomes therefore remains inconclusive.

Other agents complicate any simple classification. Dexmedetomidine, a selective alpha2-adrenergic agonist, blunts sympathetic and neuroendocrine stress responses and reduced circulating stress hormones and IL-6 in tumor-bearing mice, yet rodent studies have reported both increased and decreased metastatic burden depending on dose and model, and clinical outcome data are similarly mixed. Etomidate suppressed PD-L1 expression and improved antitumor immunity in hepatocellular carcinoma models but enhanced migration in colorectal cancer models, underscoring lineage dependence. Opioids engage mu-opioid receptors on immune cells; morphine suppresses NK cytotoxicity in humans and may activate pro-angiogenic signaling, whereas tramadol appears comparatively immune-sparing. Observational studies linking opioid exposure to recurrence point in conflicting directions across cancer types, and associations between opioid use and poorer immunotherapy response are vulnerable to confounding by pain burden and disease severity. Volatile anesthetics have been associated with blunted interferon-driven NK augmentation, T and B cell apoptosis and higher pro-tumor cytokines and matrix metalloproteinases in breast surgery, yet a large population-based study of stage III breast cancer reported lower mortality with inhalational maintenance, illustrating how context can invert apparent signals.

Regional and neuraxial techniques, including epidural and paravertebral blockade, are framed not as standalone anti-recurrence interventions but as components of a stress-attenuating bundle. Combined general and epidural anesthesia has been associated with increased intratumoral CD8-positive T-cell infiltration, reduced FOXP3-positive cell accumulation and lower postoperative inflammatory markers in lung and gastric cancer studies, and thoracic epidural analgesia reduced IL-6, norepinephrine, cortisol and ACTH during esophagectomy. Local anesthetics add direct biological signals: ropivacaine suppressed invasion through NaV1.5 channel effects, bupivacaine inhibited mitochondrial respiration and RhoA/ROCK-mediated migration in gastric cancer cells, and perioperative lidocaine reduced lung metastases in a murine breast tumor model. Randomized evidence, however, has not shown a stable recurrence benefit from anesthetic technique alone, and the authors emphasize that analgesia and recovery remain the most reliable benefits of regional approaches.

Pharmacologic adjuncts targeting the axis itself are attracting growing interest. Because prostaglandin E2 signaling through EP2 and EP4 receptors drives myeloid immunosuppression, perioperative NSAIDs or COX-2 inhibitors may partially relieve constraints on effector T and NK cells, and in vivo work shows COX inhibition can restrain tumor growth and alter PD-L1 expression and myeloid composition within tumors, although a single preoperative ketorolac dose did not improve disease-free survival in high-risk breast cancer. Beta-blockade combined with COX-2 inhibition improved markers of malignant potential, reduced epithelial-to-mesenchymal transition and remodeled immune infiltrates in a phase II breast cancer trial, and the PROSPER trial in pancreatic surgery confirmed safety with preliminary favorable signals. Immunonutrition, particularly omega-3 fatty acids that serve as precursors for pro-resolving lipid mediators, may further support inflammatory control and tissue repair within enhanced recovery pathways.

The review closes with an executable framework for individualized anesthetic planning built around three phases. Preoperatively, clinicians are encouraged to stratify risk using inflammatory and nutritional trajectories such as CRP-to-albumin ratios, neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, and, in selected cases, circulating tumor DNA with standardized sampling windows. Intraoperatively, priorities include high-quality opioid-sparing multimodal analgesia, appropriate regional techniques, stable hemodynamics, normothermia and balanced fluid management, while avoiding unnecessary anesthetic depth. Postoperatively, trend-based monitoring should prompt early pain reassessment, early enteral nutrition and mobilization to shorten the duration of stress and inflammatory exposure. Embedded within ERAS pathways, the authors argue, anesthetic management becomes an integrated component of perioperative oncologic care: no single drug or technique constitutes an anti-recurrence strategy, but reducing stress peaks, limiting avoidable immunosuppressive exposure and accelerating recovery may collectively narrow the biological window through which cancer can exploit its own surgery.

Subject of Research: The perioperative stress–inflammation–immunosuppression axis and its influence on tumor progression and anesthetic management in cancer surgery

Article Title: Perioperative stress–inflammation–immunosuppression axis and tumor progression: mechanistic integration and anesthetic management strategies

Article References: Ye, L., Shen, H., Lin, J., Pei, S., Lin, F., Li, X., Chang, E., & Pan, L. (2026). Perioperative stress–inflammation–immunosuppression axis and tumor progression: mechanistic integration and anesthetic management strategies. Holistic Integrative Oncology, 5(1), Article 63. https://doi.org/10.1007/s44178-026-00280-x

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00280-x

Keywords: perioperative stress, surgical inflammation, immunosuppression, tumor progression, anesthetic management, natural killer cells, myeloid-derived suppressor cells, regulatory T cells, neutrophil extracellular traps, regional anesthesia, opioid-sparing analgesia, ERAS pathways