Review of the Effects of Anesthetic Techniques and Medications on the Immune Response During the Perioperative Period.

Introduction
Immunology is a relatively new area of medical science that, for many years, was considered an integral part of microbiology. The term originates from the Latin word immunis, which translates to “free from.” Modern immunology focuses on the mechanisms that enable the body to differentiate between its own cells and foreign substances, identify immune disorders, and counteract immunological challenges such as infections, allergic reactions, and autoimmunity. The immune system functions closely in conjunction with the nervous system, shaping the body’s interactions with its surroundings. Understanding how the immune system functions affects diagnostic and therapeutic decisions in various clinical fields [1].
The body’s immunity is based on 2 complementary systems: nonspecific (natural, innate) immunity and adaptive (acquired) immunity. Physiologically, these systems function collaboratively to provide efficient immune protection. Innate immunity is activated first, serving as the primary defense against pathogens, and is responsible for the rapid identification and elimination of threats. When the innate immune response is insufficient, more precise mechanisms of adaptive immunity are activated, which not only protect against pathogens but also contribute to the formation of immunological memory [2].
General anesthesia and its effect on the immune system are becoming increasingly significant in the field of anesthesiology. Every surgical procedure presents not only a physical challenge to the body but also a significant immune response stimulus. Current research suggests that anesthesia modulates the immune response, affecting both inflammation and the body’s ability to protect against infections. It may also influence the prognosis of patients with cancer [1,3]. Various perioperative factors, including anesthetic agents and surgical tissue trauma, have been shown to influence immune function; their immunomodulatory effects differ depending on the clinical context and can elicit either pro-inflammatory or anti-inflammatory responses [4]. General anesthesia, particularly when combined with the physiological stress of surgery, can compromise immune function through direct effects on immune cells or via activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. In patients with cancer, such anesthetic-induced immunosuppression, including impaired natural killer (NK)-cell and lymphocyte activity, can promote the proliferation and metastasis of residual tumor cells, highlighting the critical importance of understanding how anesthetics influence perioperative immune responses [1].
One of the key issues regarding the relationship between anesthesia and the immune system is systemic inflammatory response syndrome (SIRS). This is the body’s dynamic response to surgical trauma, which, if not properly managed, can result in severe complications, such as organ failure [5]. SIRS occurs due to the strong activation of inflammatory mediators such as interleukins and interferons, making anesthesia not only a tool for pain control but also a regulator of the immune system’s response [6].
Some anesthetics can have immunosuppressive effects, which diminish the body’s capacity to protect against infections and cancer. On the other hand, certain anesthesia techniques, such as regional anesthesia, may affect the immune system to a lesser extent and, in the case of oncology patients, could potentially have a positive influence on managing the disease [7]. In patients undergoing cancer surgery, regional anesthesia has been considered as an alternative to general anesthesia due to its ability to support perioperative immune function and potentially improve long-term postoperative outcomes [7]. This article aims to review the effects of anesthetic techniques and medications on the immune response during the perioperative period.

The Immune System’s Structure and Functions
The immune system plays a crucial role in maintaining the body’s homeostasis, protecting against pathogens, and eliminating abnormal cells, including cancer cells. It consists of numerous organs, cells, and molecules that collaborate to recognize and neutralize threats [8].

Lymphatic Organs
Lymphatic organs are divided into primary and secondary organs. Primary lymphatic organs include the bone marrow and the thymus, which are responsible for the development and differentiation of lymphocytes [1]. The thymus plays a key role in T-cell selection, eliminating autoreactive cell clones, thereby preventing the development of autoimmune diseases. Secondary lymphatic organs, such as the spleen, lymph nodes, and mucosa-associated lymphoid tissue, are responsible for antigen presentation and immune cell activation [9].

Classes of Immunoglobulins
Immunoglobulins (Ig), also known as antibodies, are proteins produced by B lymphocytes that act as a defense against pathogens. There are 5 main classes of immunoglobulins: IgG, IgA, IgM, IgE, and IgD. IgG is the most prevalent class of antibody found in the serum, responsible for providing long-term immunity and pathogen neutralization. IgA, on the other hand, is mainly present in mucous secretions, protecting mucous membranes against infections. It is important to note that partial immunodeficiencies most often concern the production of IgG and IgA, resulting in epithelial diseases, such as rhinitis and periodontal disease, which are relatively mild. However, serious pathologies can also arise, such as severe pneumonia, particularly in patients treated in intensive care units. IgM is the first line of defense, produced at the beginning of the immune response. IgE plays a role in allergic reactions and the antiparasitic response, while IgD is involved in the activation of B lymphocytes [10] (Table 1).

Granulocytes and Cytokines
Granulocytes are the first line of innate defense and consist of neutrophils, eosinophils, and basophils. They are also considered new additions to the antigen-presenting cell group.
Neutrophils make up the largest group within the granulocyte family and play a key role in preventing bacterial infections. Moreover, neutrophils can act as antigen-presenting cells. This ability is supported by findings that the presence of certain cytokines, such as interferon gamma (IFN-γ) or granulocyte-macrophage colony-stimulating factor, can trigger the expression of major histocompatibility complex (MHC)-II and costimulatory molecules such as cluster of differentiation (CD) 80 or CD86 on their surface.
Eosinophils participate in the antiparasitic and allergic responses. It is suggested that eosinophils might work as antigen-presenting cells. They can take in and process antigens and send them to lymphoid organs. In the resting state, eosinophils lack MHC-II molecules; however, cytokines can induce MHC class II production. Unlike neutrophils, eosinophils exposed to parasite antigens can present these antigens to memory T cells, activate naïve T cells, and promote Th2 polarization of naïve T cells. However, more research is needed to fully understand the antigen-presenting functions of eosinophils [3,10].
Basophils support allergic reactions. Recent evidence suggests that human basophils have the potential to function as antigen-presenting cells under certain conditions. A study in mice demonstrated that basophils can acquire MHC–peptide complexes from professional antigen-presenting cells via trogocytosis, a process mediated by intercellular interactions between molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1. Additionally, increased MHC-II expression on basophils has been observed in patients with systemic lupus erythematosus. These findings indicate that, similar to neutrophils and eosinophils, human basophils can gain antigen-presenting cell–like functions in inflammatory or disease contexts [3,10]. The activity of these basophils is regulated by cytokines, signaling proteins of the immune system. Interleukins (eg, IL-6, IL-10) and interferons (IFN-α, IFN-γ) modulate the immune response by influencing the proliferation, differentiation, and function of immune cells [3].

The Complement System and the Inflammatory Response
The complement system is a complex plasma protein system that participates in the body’s defense against pathogens. There are 3 ways in which it can be activated: (1) the classical pathway, which is activated by antigen-antibody complexes; (2) the alternative pathway, which is activated directly by pathogen surfaces; and (3) the lectin pathway, which is initiated by the binding of lectins to specific sugars on the surface of microorganisms.
Complement activation leads to pathogen opsonization and leukocyte chemotaxis and targets cell lysis via the membrane attack complex. Furthermore, complement elements such as C3a and C5a function as anaphylatoxins, exacerbating inflammatory processes by stimulating histamine secretion and attracting leukocytes to the site of infection. In the context of anesthesiology, it is important to consider the possibility that anesthetic medications may affect complement activation, which might alter the body’s inflammatory response [5]. The inflammatory response is a coordinated process that begins when the immune system detects a threat. Three key stages exist. First, in the initiation phase, there is activation of pattern recognition receptors on immune cells, resulting in the production of proinflammatory cytokines (eg, tumor necrosis factor alpha [TNF-α], IL-1β). Second, in the amplification phase, there is recruitment of leukocytes to the site of inflammation and increased production of inflammatory mediators. Third, in the decision phase, there is elimination of the pathogen or repair of damaged tissue, frequently aided by anti-inflammatory cytokines (eg, IL-10, transforming growth factor beta).
In the body’s reaction to surgical trauma, the inflammatory response is a crucial line of defense. The activation of both the innate and adaptive immune systems during this process results in a comprehensive immune response. The effect of anesthetic drugs on the modulation of this reaction is a crucial topic in anesthesiology, and it can have significant clinical implications. In this article, we aim to discuss the mechanisms of inflammatory response and immunomodulatory effects of anesthetic agents in the context of surgical procedures [1,3,5,7,11].

Activation of Innate and Adaptive Immunity in Response to Surgical Injury

Initial Phase: Activation of Innate Immunity
Surgical injury causes tissue damage, leading to the release of damage-associated molecular patterns (DAMPs). These DAMP molecules are detected by pattern recognition receptors, such as Toll-like receptors, initiating a signaling cascade leading to the activation of macrophages, dendritic cells, and neutrophils. This results in the secretion of proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, along with the activation of complement and recruitment of additional immune cells [1,5].

Developmental Phase of the Immune Response: Activation of Adaptive Immunity
In response to proinflammatory signals, dendritic cells present antigens to T lymphocytes, leading to their activation. CD4+ T lymphocytes differentiate into T helper (Th) 1, Th2, and Th17 subpopulations, which modulate the immune response. CD8+ T lymphocytes, in turn, play a key role in eliminating infected or damaged cells. Furthermore, activated B lymphocytes produce specific antibodies that support the elimination of pathogens and dead cells. Regulatory T lymphocytes (Tregs) play a crucial role in regulating excessive inflammatory responses, preventing immune activation, and limiting tissue damage [1,5] (Figure 1).

General Anesthesia as a Modulator of the Inflammatory and Immune Response in Surgical Patients
General anesthesia is an anesthetic technique designed to induce a controlled state of unconsciousness, analgesia, and areflexia, essential during complex surgical procedures. General anesthesia administered during surgical procedures has a significant impact on the immune system. Anesthetic agents, such as inhalational and intravenous anesthetics, can affect various aspects of the immune response, both on the cellular and molecular levels. Anesthetics, such as isoflurane, propofol, and cisatracurium, can modify the activity of T and B lymphocytes, impacting their proliferation and function. Anesthesia also changes the production of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, which are essential in the inflammatory response. The immune response may be suppressed, which can increase the risk of postoperative infections because the immune system is unable to respond effectively to pathogens. Contrarily, in certain instances, anesthesia can trigger immune reactions, such as mast cell activation, which can result in pseudoallergic responses, as described in studies with cisatracurium. Such reactions can also interfere with wound healing and induce inflammation [7,12,13].

Immunomodulatory Mechanisms of Action of General Anesthesia
General anesthesia exerts a significant influence on the immune system by altering the activity of immune cells and adjusting the inflammatory response. General anesthetics, whether administered through inhalation or intravenously, can affect immune cell signaling pathways, such as NF-κB (nuclear factor kappa B), MAPK (mitogen-activated kinases), JAK/STAT (Janus kinase–signal transducer and activator of transcription), and mTOR (mechanistic target of rapamycin). Recent mechanistic insights indicate that the signaling pathway of mTORC1 (mechanistic target of rapamycin complex 1) and NF-κB (nuclear factor kappa-B) is not merely parallel; rather, it includes direct interaction, which may mediate how anesthetic agents influence immune trajectories. For instance, in hypoxia-induced pulmonary artery smooth muscle cells, mTORC1 activation preceded NF-κB phosphorylation. Immunoprecipitation and kinase assays demonstrated that mTOR directly interacted with IκB kinase (IKK) α/β, phosphorylating them at Thr23 (IKKα) or Thr559/Ser634 (IKKβ), thereby increasing IKK activity, IκBα degradation, and NF-κB nuclear translocation [14]. Translating this to the perioperative immune context, inhalational or intravenous anesthetics (eg, isoflurane, propofol) that suppress the upstream PI3K/AKT/mTOR axis may reduce mTORC1 signaling, consequently leading to decreased phosphorylation of IKK and diminished activation of NF-κB. The result is a decrease in the transcription of NF-κB target genes (including TNF-α, IL-1β, IL-6) and reduced leukocyte activation/proliferation. Conversely, failure to preserve mTOR-NF-κB signaling might lead to excessive immunosuppression (lowered antigen-presentation, diminished NK-cell function, reduced T-cell activity), which may heighten the risk of postoperative infections. The implication is that anesthetic technique modulates immune cell fate via the mTOR–NF-κB axis; for example, regional anesthesia or drugs that inhibit mTOR/NF-κB less may better preserve immune competence. Incorporating this mechanistic layer enhances the discussion beyond descriptive changes in cytokine levels and links actual pathway interactions to clinical immunomodulation [14,15]. An additional layer of mechanistic complexity arises from the interaction between mTOR signaling and the JAK/STAT signaling pathway cascade in immune cells. The review by Delgoffe and Powell describes how mTOR and STAT pathways converge: mTORC1/2 affects the activation of STAT1, STAT3, and STAT5, while STATs feed back into nutrient-sensing and translation programs [16]. In T cells, for instance, mTORC1 supports STAT4/STAT3 activation downstream of IL-12/IL-6, thereby facilitating the differentiation of Th1/Th17. Conversely, mTORC2 supports STAT6 activation and Th2 differentiation, whereas reduced mTOR signaling favors FOXP3+ Treg development [17]. In relation to the interactions between anesthesia and the immune system, if certain anesthetic agents reduce mTOR signaling, then STAT activation may be weakened; for instance, impaired STAT5 or STAT3 reduces NK-cell activation or memory T-cell proliferation. Simultaneously, mTOR inhibition may skew differentiation toward Tregs or non-cytotoxic phenotypes, potentially dampening anti-tumor immunity in perioperative cancer patients. Therefore, the selection of anesthetics may alter the balance of immune cell subsets by modulating mTOR-JAK/STAT coupling rather than simply reducing cytokine production. Acknowledging this linkage encourages a more detailed perspective: anesthesia not only suppresses immune cells but also interferes with the interactions of signaling networks (mTOR–JAK/STAT–NF-κB) that control immune cell identity and function [14,18,19].

Methodological Considerations and Limitations
As research on how anesthesia methods affect immune responses increases, it is important to take a careful approach to the strength and reliability of the methods used in many studies. Numerous immunological investigations to date rely predominantly on animal models or in vitro systems, which allows controlled mechanistic exploration but limits direct translation to human clinical situations [20]. Animal immune systems vary significantly from those in humans; for example, they differ in aspects such as NK-cell subsets, cytokine kinetics, and tumor microenvironments. Therefore, the results obtained in these studies may not directly apply to the human situation during the perioperative period. From the human perspective, many clinical observational studies are retrospective and conducted at a single center, often lacking sufficient power. Common challenges include small sample sizes, brief follow-up periods, and variability in patient populations and types of surgeries [21,22]. For example, Jansen et al emphasize that “the existing literature includes mainly hypothesis-forming retrospective studies and small randomized trials with many methodological limitations” [21]. Similarly, the 2023 meta-analysis conducted by Konstantis et al found only 6 pertinent randomized controlled trials related to gastrointestinal cancer surgery, highlighting that the evidence remains inconclusive due to sample size and design issues [22]. Additional challenges include the variability in anesthetic drug dosages and combinations (inhalational vs intravenous, adjuncts), inconsistent immune-outcome endpoints (NK-cell counts, cytokine levels, lymphocyte subsets), short perioperative sampling windows (typically only the initial 24–72 hours), and a lack of extensive long-term immune or oncological follow-up [23]. Taken together, these limitations require that we interpret the immunomodulatory and oncologic implications of anesthetic techniques with caution. Future studies should prioritize robust randomized controlled trials, standardized immunologic endpoints, longer follow-up, stratification by tumor type and patient immune status, and mechanistic human translational endpoints, to narrow the translational gap.

Effects of Inhalation Anesthetics on the Immune System
Inhaled anesthetics consist of a diverse group of agents with distinct chemical and pharmacological characteristics. They can be categorized into 3 main types: halogenated volatile ethers, such as isoflurane, sevoflurane, desflurane, and enflurane; halogenated alkanes, such as halothane; and inorganic gases, such as nitrous oxide and xenon [13].

Halogenated Volatile Ethers
Inhalation anesthetics such as isoflurane, sevoflurane, and desflurane have the ability to interact with gamma-aminobutyric acid type A (GABA-A) and N-methyl-D-aspartate (NMDA) receptors. These receptors are involved in regulating neuronal activity, and when activated by anesthetics, they inhibit the secretion of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β [19]. Sevoflurane, isoflurane, and desflurane all reduce systemic vascular resistance, which usually leads to a drop in mean arterial pressure. Additionally, these agents tend to increase the respiratory rate while reducing tidal volume [24]. Below, we characterize the effects of selected inhalational anesthetics on the immune system.
Isoflurane is a derivative of methyl ethyl ethers and exhibits several characteristics desirable in an anesthetic agent. It is chemically stable, nonflammable, has low blood solubility, and undergoes minimal metabolic degradation [25]. Isoflurane, for example, by interacting with the GABA-A receptor, inhibits the production of messenger RNA for proinflammatory cytokines, resulting in reduced activity of dendritic cells and T lymphocytes. This weakens the body’s immune response to pathogens and suppresses the inflammatory response. Reduction in the activity of the NF-κB pathway, a key regulator of inflammation, results in lower production of proinflammatory cytokines, which may reduce the body’s defense responses [19]. Volatile anesthetics exhibit differential effects on the leukocyte integrin macrophage-1 antigen (Mac-1). Isoflurane, unlike sevoflurane, inhibits Mac-1 binding to ICAM-1 by interacting with a cavity located beneath the α7 helix of the αM I domain. This suggests that the 2 agents may have distinct immunomodulatory profiles [26]. In addition, at equivalent anesthetic potencies, isoflurane but not sevoflurane induces cytotoxic effects in rat PC12 pheochromocytoma cells and primary cortical neurons, accompanied by a reduction in the Bcl-2/BAX ratio [27]. One study showed that isoflurane enhances hypoxia-inducible factor 1 (HIF-1) expression in prostate cancer cells through the PI3K/AKT/mTOR pathway, promoting invasion and migration, while propofol can inhibit this pathway, highlighting its potential benefit in tumor surgeries. The genotoxic effects of inhaled anesthetics are also linked to postoperative tumor recurrence [28].
Sevoflurane belongs to the class of fluorinated methyl isopropyl ethers. It has been associated with decreased levels of S100β, NOX2, and NOX4 proteins, compared with propofol, while also demonstrating genotoxic effects on bronchoalveolar cells and increased plasma levels of 8-hydroxy-2′-deoxyguanosine [25]. Compared with isoflurane and desflurane, sevoflurane is characterized by low airway pungency and typically does not provoke respiratory irritation during induction. Despite its favorable tolerability profile, sevoflurane is metabolized more rapidly, resulting in increased plasma concentrations of inorganic fluoride, a metabolite associated with potential nephrotoxic effects [29].
Desflurane is a fluorinated methyl ethyl ether structurally similar to isoflurane, differing only by the substitution of a fluorine atom in place of the α-ethyl chlorine. Some studies suggest that desflurane may exert genotoxic effects and disrupt cellular redox balance. Additionally, when compared with sevoflurane in patients undergoing elective cesarean delivery, desflurane was associated with significantly higher postoperative levels of oxidative stress markers, including lipid hydroperoxides and total oxidant status, indicating a less favorable oxidative profile [13]. Desflurane is known for its high pungency, which frequently leads to airway irritation. During the induction of general anesthesia, it can provoke adverse respiratory responses such as coughing, breath-holding, increased salivation, or even laryngospasm in approximately 30% to 40% of patients [29].
Enflurane (2-chloro-1-(difluoromethoxy)-1,1,2-trifluoroethane) is an inhaled general anesthetic. Its anesthetic potency is about half that of halothane. Adverse effects reported in patients include malignant hyperthermia, seizures, arrhythmias, respiratory depression, and hypotension. Healthcare workers can be exposed to enflurane occupationally. The primary target organ for enflurane is the central nervous system, where it can notably impair psychomotor function [30]. Enflurane, along with sevoflurane and isoflurane, has been shown to inhibit the release of key proinflammatory cytokines, such as IL-1β and TNF-α, from NK cells activated by tumor cells. Moreover, enflurane directly contributes to immunosuppression by impairing the function of immune effector cells and cytokine production. It also enhances the expression of HIF-1 and matrix metalloproteinases, factors associated with tumor progression and increased malignancy [18].

Halogenated Alkanes
Halothane is associated with slower induction and intubation than is sevoflurane. Patients receiving halothane experienced more adverse effects during induction, including coughing, breath-holding, salivation, rigidity, and movement. These findings highlight several clinical disadvantages of halothane in comparison with newer agents, such as sevoflurane [31]. Halothane, along with isoflurane, diminishes NK-cell responsiveness to interferon stimulation in both in vitro and in vivo settings, which may facilitate metastatic progression. It has also been demonstrated that halothane reduces the number of NK cells in circulation, indicating its broader inhibitory effect on innate immune function [32]. Halothane supports the immune response to influenza by modulating type I interferon activity and helping prevent secondary bacterial pneumonia. In animal models, it enhances the early recruitment of neutrophils (polymorphonuclear leukocytes) and protects macrophage antibacterial function from being suppressed by antiviral cytokines, such as type I IFNs and IFN-γ [33].

Inorganic Gases
Nitrous oxide, also known as dinitrogen monoxide, is a nitrogen oxide with anesthetic effects at lower concentrations than those needed for general anesthesia. It provides rapid-onset, short-duration analgesia and does not increase the risk of myocardial infarction after non-cardiac surgery. A detrimental effect of nitrous oxide exposure is its ability to oxidize and deactivate vitamin B12 [34]. It inactivates vitamin B12 by oxidation, impairing its role as a coenzyme. In individuals with vitamin B12 deficiency, there is a decrease in the number of CD4+ T cells, and more notably, a reduction in CD8+ T cells and NK-cell activity. Nitrous oxide can cause gas expansion, leading to increased pressure in enclosed air-filled areas, such as in bowel obstruction or pneumothorax [25].
One study revealed the influence of inhalation anesthetics affecting the IgA and IgM levels, which indicated a reduction in humoral immunity in patients with breast cancer. This could have an effect on the outcome of surgery and long-term outcomes in cancer treatment [35] (Table 2).

Effects of Intravenous Anesthetics on the Immune System
Commonly used intravenous anesthetic agents in clinical settings include dexmedetomidine, propofol, ketamine, etomidate, midazolam, and remimazolam [36].
Propofol, or 2,6-diisopropylphenol, is administered intravenously to induce and maintain anesthesia. Propofol can modulate mast cell function and alter the secretion of cytokines, such as IL-4, IL-5, and TNF-α, potentially impacting the characteristics of the postoperative inflammatory response [10]. Propofol was found to markedly suppress NF-κB activity and reduce the levels of associated pro-inflammatory cytokines, including IL-1β and IL-18, while also attenuating TNF-α–induced inflammatory responses [23].
Dexmedetomidine is a potent and highly selective α2-adrenergic receptor agonist that provides sedation, anxiolysis, and analgesia, with the advantage of producing minimal respiratory suppression. Dexmedetomidine exerts immunomodulatory effects by attenuating proinflammatory signaling, reducing cytokine release, and altering leukocyte activity, alongside its other cellular actions, such as regulating neurotransmitters, oxidative stress, and apoptotic pathways [36]. An animal study demonstrated that dexmedetomidine effectively blocks the activation of the insulin-like growth factor 2 signaling pathway in ovarian cancer models, leading to improved immune function and reduced invasion and migration of ovarian cancer cells [23].
S-ketamine, the S-enantiomer of ketamine, functions as a noncompetitive NMDA receptor antagonist and demonstrates a wide range of therapeutic actions, including analgesia, opioid-sparing anesthesia, antidepressant activity, and modulation of immune responses. Nevertheless, when administered with sevoflurane during radical esophageal cancer surgery, it did not produce notable changes in postoperative cellular immune function [37]. Ketamine demonstrated a strong anti-inflammatory effect by inhibiting NF-κB expression, lowering IL-1β and IL-18 production, and mitigating TNF-α–mediated inflammatory activity [23].
Etomidate is a non-barbiturate intravenous anesthetic that produces anesthesia by modulating GABA-A receptors [38]. Etomidate may help reduce perioperative immune and hormonal stress by modulating immune cell profiles and cytokine release. Compared with controls, patients receiving etomidate showed higher CD4+ T cell counts and CD4/CD8 ratios, along with lower levels of IL-6, TNF-α, and IL-8, and increased IL-10, suggesting an anti-inflammatory and immunoprotective effect during surgery [39].
Midazolam is a benzodiazepine delivered intravenously, used for conscious sedation in minor procedures and as a supplementary agent in general anesthesia. Midazolam reduces immune responses triggered by lipopolysaccharides in human macrophages through the activation of translocator protein signaling. The inhibition of macrophage function may be linked to the harmful adverse effects of benzodiazepines observed in critically ill patients [40]. Midazolam has been shown to reduce lipopolysaccharide-induced upregulation of CD80 in THP-1 and primary monocyte-derived macrophage cells, as well as to decrease the secretion of IL-6 and nitric oxide. It suppresses the activation of NF-κB/AP-1 and MAPK signaling pathways in human THP-1 cells, thereby inhibiting their immune function [23].
Remimazolam is a new, ultra–short-acting benzodiazepine. Remimazolam anesthesia leads to a more effective preservation of perioperative immune function than does propofol, as evidenced by significantly elevated levels of NK cells, CD3+, and CD4+ lymphocytes, both immediately after surgery and 24 hours later [41] (Table 3).

Effects of Muscle Relaxants on the Immune System
Muscle relaxants are commonly used in anesthesiology to guarantee proper relaxation of the skeletal muscles during surgical procedures. The most frequently used substances are cisatracurium, rocuronium, and vecuronium. These agents act by blocking nicotinic receptors in the neuromuscular junction, thereby inhibiting the conduction of nerve impulses to the muscles, resulting in muscle relaxation. Although their primary purpose is to facilitate surgical procedures, these drugs also have effects on the immune system, which can be significant regarding complications that arise after surgery [42–45].
Cisatracurium, a widely used muscle relaxant, can cause pseudoallergic reactions due to the activation of Mas-related G protein–coupled receptor X2 receptors on mast cells. Activation of these receptors leads to mast cell degranulation and the release of inflammatory mediators, such as histamine and proinflammatory cytokines, resulting in anaphylactoid reactions. Studies have shown that cisatracurium can cause such reactions, which can have serious consequences for patient health, particularly during and after surgery. Such reactions occur when cisatracurium interacts with mast cells, causing inflammation in the body that can result in serious complications in patients with weakened immune systems [7,46].
In contrast to cisatracurium, other muscle relaxants, such as rocuronium and vecuronium, have a lesser effect on mast cells and are less prone to induce pseudoallergic reactions. Nonetheless, rocuronium and vecuronium can affect other components of immune function, including T- and B-lymphocyte activity. Muscle relaxants can modulate the production of cytokines, which play a key role in the inflammatory response and in regulating immune function. Long-term use of these drugs during surgical procedures can result in alterations in cytokine profiles, potentially affecting the immune system, notably in immunocompromised patients [13].
Cisatracurium, along with other muscle relaxants, can influence the production and secretion of inflammatory cytokines, which consequently shape the body’s overall inflammatory response. Research has indicated that administering cisatracurium in animal models leads to increased levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, which is particularly evident in the context of immune system disorders, such as sepsis [46].
The secretion of proinflammatory cytokines in response to muscle relaxants can lead to increased inflammatory responses, potentially hindering wound healing and increasing the risk of postoperative infections. Furthermore, muscle relaxants influence the activity of immune cells, including macrophages and neutrophils, which are essential in initiating and regulating the inflammatory response in humans. Once activated, macrophages can secrete significant amounts of cytokines, which enhance the inflammatory response, which can result in chronic tissue damage during prolonged inflammation [46].

Effects of Drugs Reversing Neuromuscular Blockade on the Immune System
Sugammadex is a modified γ-cyclodextrin used to reverse neuromuscular blockade induced by rocuronium and vecuronium, and it is increasing in clinical use. Sugammadex was approved by the U.S. Food and Drug Administration in 2015 [47,48]. Research has indicated that it leads to quicker recovery from neuromuscular blockade and results in fewer postoperative cardiac and pulmonary complications when compared to glycopyrrolate and neostigmine. Despite its recognized efficacy, adverse reactions have been reported, including nausea, vomiting, pain, hypotension, bradycardia, interactions with other medications (eg, as a steroid binder, it can lessen the effectiveness of oral contraceptives), and severe hypersensitivity, including anaphylaxis, which often occur shortly after drug administration [31]. The primary causes of perioperative anaphylaxis are antibiotics, neuromuscular blockers, latex, chlorhexidine, and blue dye, which collectively account for over 90% of occurrences [49,50]. Since these frequent allergens are usually found during the start of anesthesia or the early phases of the procedure, most anaphylaxis cases happen at the beginning of anesthesia. Anaphylaxis to medications usually given at the end of the procedure, such as ondansetron, opioid analgesics, and amide local anesthetics, is rare. Nonetheless, as the use of sugammadex grows in the United States and globally, the likelihood of anaphylaxis during the recovery and emergence stages of anesthesia also rises. The occurrence of anaphylaxis linked to sugammadex is important because cyclodextrin is a widely used molecule found in food preservatives, drug carriers, and various commercial products. Consequently, sensitization can happen even in the absence of previous exposure to sugammadex. Unfortunately, there are no recognized shared demographics or risk factors that could otherwise increase suspicion. Diagnosis can be challenging in the absence of a well-defined risk profile and becomes increasingly complicated during the recovery stage, when cardiorespiratory indicators are inherently and frequently fluctuating. Retrospective analyses have shown that these reactions can occur with both sugammadex and the sugammadex-rocuronium complex, suggesting a complex immunological mechanism that is not necessarily dependent on IgE. It is proposed that the direct mast cell activation, likely involving a hapten mechanism, may be the trigger. Therefore, skin tests for potential anaphylactic reactions must encompass assessments for the specific components of sugammadex, the sugammadex/rocuronium complex, and γ-cyclodextrin [51,52]. If any of these elements produce a positive outcome, it is advised to refrain from future use of sugammadex, regardless of whether different aminosteroid neuromuscular blockers are administered. Clinical data indicate that although these reactions are rare, their course can be severe and require immediate intervention. Given the increasing use of this drug in anesthesiology, it is necessary to conduct further analysis of its effects on the immune system and the potential development of anaphylactic reactions [48,53,54].

Effects of Regional Anesthesia on the Immune System
Regional anesthesia is gaining increasing importance not only for its benefits related to pain control but also for its effect on the immune response in the perioperative period. Unlike general anesthesia, it alleviates the stress response to surgery while limiting immunosuppression. Surgical trauma elicits local and systemic inflammatory responses, characterized by elevated levels of pro-inflammatory cytokines, including IL-6, IL-8, and TNF-α. By blocking nociceptive transmission, regional anesthesia can attenuate this inflammatory cascade. Clinical studies consistently report lower postoperative concentrations of IL-6, IL-8, TNF-α, and C-reactive protein in patients receiving regional anesthesia, compared with the concentrations of those under general anesthesia. This attenuation of cytokine release may mitigate the acute phase response, reduce the risk of sepsis and SIRS, and facilitate enhanced wound healing and recovery [55–57].
Regional anesthesia modulates the neuroendocrine response by limiting activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, leading to reduced cortisol and catecholamine secretion. This results in lower levels of proinflammatory cytokines and a more gradual shift in the lymphocyte profile, especially concerning Th1 and Th2 lymphocytes [38,57,58]. Senapathi et al found that spinal anesthesia is associated with a milder effect on the immune system, compared with general anesthesia, as evidenced by differences in the levels of lymphocytes and proinflammatory cytokines, such as IL-6 and TNF-α [58]. Certain anesthetics, surgical stress, and pain medications commonly used during anesthesia in cancer surgeries are recognized to diminish the body’s immune system. Surgical stress can exacerbate age-related immunodeficiency in elderly patients through the release of stress hormones such as cortisol, which suppress immune function. The anesthetic technique plays a critical role in modulating this response. Evidence suggests that regional anesthesia, particularly epidural techniques, may attenuate the stress-induced rise in cortisol and enhance the activity of stress-limiting immune mechanisms, thereby supporting immune homeostasis. Spinal anesthesia exerts a milder effect, with moderate cortisol elevation but preservation of immune protection. In contrast, general anesthesia is associated with higher cortisol levels and reduced activity of stress-regulatory pathways, potentially leading to glucocorticoid-induced immunosuppression [59]. In addition to any current micrometastases, the surgical excision of tumors can cause the local spread of tumor cells, which can subsequently enter the bloodstream and lymphatic system. Many elements associated with the perioperative phase, such as inflammatory and neurohumoral effects, the patient’s physical response to surgery, and the postoperative care administered, can promote the aggressiveness and dissemination of residual tumor cells. Additionally, these factors can enhance the formation of new blood vessels and stimulate tumor growth. Besides affecting tumor cells, these factors can also diminish the strength of the body’s immune system. As a result, surgical interventions and anesthesia can influence the long-term recurrence of tumors. Recent laboratory studies have demonstrated that actions taken during the surgical period can affect the recurrence or spread of tumors by altering the communication between tumor cells, the immune response, and the body’s reaction to stress. Consequently, both anesthesia and surgery can diminish immune responses and promote the formation of new blood vessels, potentially resulting in increased tumor cell growth and dissemination during the surgical period. One way in which anesthetic medications and methods can influence the immune system is by lowering the amounts of anti-inflammatory proteins and altering the behavior of NK cells. Additional research has indicated that techniques such as epidurals and paravertebral blocks can substantially decrease inflammation and prevent immune system suppression in individuals undergoing surgery for cancer. Reports suggest that there are no significant differences in tumor recurrence or treatment outcomes depending on the different types or techniques of anesthesia used. Unfortunately, the existing data from clinical studies is limited, often retrospective, involves small sample sizes, and commonly yields varied outcomes, leading to numerous inquiries with few clarifications. Moreover, this evidence presents a moderate to high likelihood of bias and is considered to be of low quality. For these reasons, it is essential to conduct randomized clinical trials to verify these results. In circumstances in which detailed clinical trial information is insufficient to provide explicit recommendations, doctors and anesthesiologists can work to determine the most effective anesthesia and pain management options for their cancer patients. This should be directed by the most trustworthy information concerning treatment outcomes and a careful evaluation of the risks and advantages customized to each patient [57,58]. Additionally, certain local anesthetics can directly affect immune cells by inhibiting the activity of macrophages and monocytes and modifying the expression of surface molecules [38]. Lidocaine, a widely used local anesthetic, has been increasingly recognized for its immunomodulatory and anti-inflammatory properties. Beyond its primary anesthetic action, accumulating evidence suggests that lidocaine can influence innate and adaptive immune responses, thereby contributing to the modulation of perioperative immune function and potentially improving surgical outcomes [59]. Bupivacaine, a long-acting amide-type local anesthetic with a high affinity for plasma proteins, has been shown to induce apoptosis in breast cancer cells. Both lidocaine and bupivacaine significantly increased apoptotic activity in MCF-7 breast cancer cells, compared with MCF-10A mammary epithelial cells. These agents activated caspases 7, 8, and 9 in MCF-7 cells, leading to nucleosome degradation and apoptosis through intrinsic and extrinsic mitochondrial pathways [28].
Regional anesthesia, through its modulation of the inflammatory and neuroendocrine response, plays an important role in the patient’s immune protection during the perioperative period. This holds significance in cancer surgery and in individuals with immune compromise. Regional anesthesia techniques, including neuraxial anesthesia and peripheral nerve blocks, have been linked to reduced cancer recurrence in preclinical and observational studies. The proposed mechanism suggests that regional anesthesia may improve oncological outcomes following cancer surgery by attenuating the neuroendocrine stress response to surgical trauma, decreasing opioid requirements, and reducing exposure to volatile anesthetics. Furthermore, regional anesthesia appears to help preserve immune function and may exert direct inhibitory effects on tumor cell activity. Experimental in vitro studies suggest that systemic lidocaine exerts a protective effect against cancer recurrence; however, supporting clinical evidence remains limited [60,61]. From an oncological perspective, the integration of these mechanistic axes (mTOR–NF-κB–JAK/STAT) is critical to perioperative immune surveillance and tumor recurrence. For example, the cytotoxic functions of NK cells and CD8+ T cells depend on metabolic reprogramming via mTOR, on STAT-mediated activation (STAT1, STAT5), and on NF-κB-driven cytokine/chemokine secretion for recruitment and survival [62]. If an inhalational anesthetic suppresses the PI3K/AKT/mTOR axis, reducing mTORC1/2 activation, this may diminish NK-cell IFN-γ production (as seen when mTOR inhibitor Torin2 reduced IFN-γ in NK cells) [62]. Simultaneously, reduced mTOR may impair IKKα/β phosphorylation, leading to reduced NF-κB activation and lower IL-6/TNF-α release, which might lessen the surgical stress inflammatory surge (beneficial in some settings) but also reduce anti-tumor immunity through fewer danger signals. Additional suppression of STAT signaling (via mTOR-JAK/STAT crosstalk) may favor Treg expansion, reducing tumor cell elimination. In summary, the immunomodulatory effect of anesthetic technique can translate into altered oncologic outcomes not only through direct immunosuppression, but also by influencing the immune cells fate, effector function, and signal-network balance (mTOR–NF-κB–JAK/STAT). Although high-quality randomized trials in cancer surgery are lacking, aligning mechanistic understanding with clinical strategy would allow tailored anesthesia, including agent, dose, and technique, particularly in patients with cancer, to preserve immune surveillance while reducing unnecessary inflammation. Identifying anesthetic protocols that maintain mTOR/NF-κB/STAT pathway integrity might represent a future approach for improving oncologic outcomes [61,62] (Table 4).

Controversial Findings and Interpretative Variability
A further barrier to constructing definitive recommendations is the inconsistent and sometimes contradictory findings across studies on how different anesthetic agents modulate the immune system. For instance, while some studies show reduced NK-cell activity or suppressed T-cell responses under volatile agents, others show no significant difference between inhalational and intravenous techniques. In one double blind randomized trial of patients with breast cancer undergoing surgery (n = 98) comparing total intravenous anesthesia (propofol) vs inhalation (sevoflurane), no difference was found in neutrophil-to-lymphocyte ratio or NK-cell counts between the groups, although differences in IgA, IgM, and C-reactive protein were seen [35]. Another systematic review of gastric and colorectal cancer surgery found no significant differences in primary immune endpoints between total intravenous anesthesia and volatile based anesthesia in 6 randomized controlled trials, concluding that “the clinical question of how the anesthetic technique choice affects the immune system and prognosis remains unresolved” [22]. Several factors can account for such variability: patient co-morbidities, tumor type and stage, timing of immune sampling, differing definitions of immune suppression, and variation in anesthetic protocols, including dose, adjuncts, neuromonitoring, and analgesia. Additionally, the immunologic effect of anesthesia may be small relative to the overriding effect of surgical stress, transfusion, hypothermia, or postoperative pain. As reported by Chalkias, “the impact of anesthetics on immune system modulation may vary and includes both pro inflammatory and anti-inflammatory effects,” emphasizing that immune effects are not uniformly suppressive [62]. In tumor surgery specifically, although retrospective data hint that total intravenous anesthesia may be associated with improved survival compared to volatile agents, Jansen et al highlight the possibility that the effect size is very minimal and confounders may predominate [21]. In our review, to account for these discrepancies, we have deliberately presented both the positive and negative findings and emphasized that the heterogeneity of results does not currently support broad clinical practice changes. Instead, a nuanced, patient specific approach is warranted: anesthetic technique selection should consider immunologic status, such as cancer and immunocompromise, but always within the broader context of surgical stress management, multimodal analgesia, and perioperative immune-support strategies.

Conclusions
Immunology in anesthesiology is a field that is becoming increasingly significant, particularly regarding how general anesthesia affects the immune system of patients undergoing surgical procedures. Anesthesia, both general and regional, influences the body’s immune response, altering inflammatory processes and adjusting defense responses. Research indicates that anesthetics, by affecting immune cell signaling pathways, can both inhibit and stimulate the immune response. This is particularly important in clinical settings, especially for patients with weakened immune systems, such as those with cancer.
General anesthesia, including inhalation and intravenous anesthetics, can inhibit the immune response, increasing susceptibility to postoperative infections. Changes in the production of proinflammatory cytokines and the activity of immune cells, such as T and B lymphocytes, influence this process. Moreover, some anesthetics, such as cisatracurium, can induce pseudoallergic reactions, which also affect the inflammatory response. Compared with general anesthesia, regional anesthesia has a more beneficial effect on the immune system, moderating the stress and inflammatory response, which could be significant for patients with cancer. Decreases in proinflammatory cytokine levels and enhanced immune response provide evidence of the potential advantages of this technique in surgery, particularly in reducing the chances of tumor spreading and improving treatment outcomes. Understanding the immunomodulatory mechanisms of general and regional anesthesia allows for more precise tailoring of anesthetic strategies, which translates into improved surgical outcomes and minimized postoperative complications.

Future Directions
Advancing our understanding of how general and regional anesthetic techniques modulate perioperative immune function is essential for refining evidence-based anesthetic strategies. Future studies should aim to delineate the specific molecular and cellular pathways influenced by different anesthetic agents, clarify the clinical relevance of these immunologic alterations across various surgical populations, and determine whether targeted anesthetic approaches can actively enhance perioperative immune resilience. Integrating mechanistic insights with large-scale clinical data may ultimately guide the development of personalized anesthetic protocols that improve surgical outcomes and reduce postoperative complications.