Opioids are commonly administered for the management of severe pain, because they can primarily target the µ, κ, δ and nociception (NOP) receptors (13). Amongst these, the µ receptor, with its two subtypes µ1 and µ2, is predominantly responsible for the key analgesic effects of opioids (14,15). In addition, they have also been implicated in opioid addiction (16). The µ1 receptor associated with central analgesia, euphoria and opioid use dependence (17). The µ2 receptor primarily mediates physiological processes, such as respiratory depression and inhibition of gastrointestinal motility (18). By contrast, the κ receptor and its three subtypes (κ1, κ2 and κ3), which are also involved in analgesia and sedation, exhibit relatively milder respiratory depression effects compared with these exerted by the µ receptor (19). The δ receptor is associated with anti-anxiety and antidepressant effects, whilst the NOP receptor is involved in regulating various responses, including reward and depression (20).

Opioid receptors, including µ, δ, κ and NOP, are involved in regulating a number of physiological activities, such as analgesia, memory modulation, respiratory control and angiogenesis (21,22). A number of studies have suggested that opioids may contribute to the oxidative stress response within the breast cancer and human neuroblastoma tumor microenvironment (23-25), promoting the production of reactive oxygen species (ROS) (26,27). As a major mutagen, ROS can increase the risk of tumor development in opioid users (23,28). Additionally, opioids may exacerbate the oxidative imbalance, particularly in patients with cancer who frequently exhibit heightened oxidative stress due to concurrent inflammation (29). This suggests that opioids could cause greater harm to patients with cancer compared with healthy individuals. Table I presents a functional overview of opioid receptors in the tumor immune microenvironment.

Opioids can modulate immune functions through both direct and indirect pathways, influencing the body's response to tumor cells (9,30). Direct effects occur when opioids bind to opioid receptors on immune cells, directly regulating their physiological activity, which is primarily mediated through µ receptors. By contrast, indirect effects are mediated through the inhibitory effects of opioids on the central nervous system, affecting various receptors within the sympathetic nervous system. They can involve D1 receptors, ultimately affecting peripheral Y1 receptors to inhibit spleen NK cell cytotoxicity (9,30). Previous animal studies and studies on human CD3+ T cell and leukemic T-cell lines have demonstrated that µ receptor activation can suppress the activity of NK cells and inhibit the mitogenic responses of T cells (31-33). In addition, it can also suppress the mitogen responses of B cells in mice following an in vivo administration (34).

Existing evidence suggests that opioids may have dual effects on tumor progression, depending on the concentrations applied and the tumor cell heterogeneity profile (35,36). Previous studies on morphine have indicated that µ receptor expression in Lewis lung carcinoma cells may be crucial to these mechanisms, influencing tumor growth and metastasis by regulating apoptosis and VEGF signaling. As a result, opioid antagonists may represent a novel therapeutic option for cancer treatment (9,12,34). The following sections discuss the mechanisms of various opioid receptors and their potential effects on the immune system.

µ receptor agonists are considered immunosuppressive agents that can hinder the body's ability to combat cancer cells, particularly by promoting angiogenesis (37). Morphine, as a µ receptor agonist, also shows an agonistic effect on δ and κ receptors. However, it shows a low drug selectivity on δ and κ receptors compared with µ receptors (38). Therefore, morphine is primarily the predominant µ receptor agonist. Previous studies have shown that activation of morphine-induced µ receptors can promote breast cancer cell proliferation both in vivo and in vitro (37,39). Morphine can also regulate the polarization of macrophages toward an M1 or M2 (alternative) activation state in vitro. A previous study on murine bone marrow cells documented that morphine can inhibit macrophage M1 polarization in vitro (40). In addition, morphine was found to inhibit M2 macrophage (alternative) activation in vitro, including the processes of antigen uptake and caused morphological changes, such as decrease in perimeter, area and aspect ratio, increase in roundness, circularity and solidity (40). An experimental study on breast cancer indicated that morphine can decrease macrophage M2 polarization through blocking the activation of IL-4, which may lead to breast cancer progression (41). However, other studies on morphine have indicated that it can inhibit tumor invasiveness by modulating the production of macrophage proteases in the tumor microenvironment. Specifically, morphine affects the production of certain proteins such as inhibiting the production of MMP-9 and MMP-2 by inhibiting the nitric oxide (NO)/NO synthase (NOS) system] in MCF-7 breast cancer cells and pancreatic cancer (42,43). The NO/NOS system serves an important role in tumor progression, NO, as an important bioregulatory mediator in the human body, is produced in the body by the action of NOS, exhibiting the function of inducing extracellular matrix degradation (44,45). MMP-9 breaks down the extracellular matrix (ECM) and the basement membrane, which are structural components that provide physical barriers to multiple tumor cells, including giant cell tumor of bone (GCTB), non-small cell small lung cancer (NSCLC) and breast cancer. By degrading these barriers, MMP-9 enables tumor cells to invade surrounding tissues and spread to other parts of the body, increasing tumor invasiveness and metastasis (46,47). Therefore, by inhibiting the production of MMP-9 by inhibiting the NO/NOS system, morphine may exhibit an inhibitory function against tumor metastasis and invasiveness.

Previous studies have demonstrated that morphine can exert a dual effect on the proliferation of pancreatic cancer cells. In murine experiments, the tumor volume was found to be significantly increased in the low-dose morphine group (at doses of 0.5 mg/kg), whereas it was significantly smaller in the high-dose morphine group (at doses of 5 mg/kg) compared with that in the control group. The underlying mechanism was proposed to be mediated through the p38/JNK pathway. Specifically, low concentrations of morphine in this concentration led to an increase in phosphorylated JNK, whilst the phosphorylation of p38 was reduced. By contrast, higher concentrations of morphine reversed these aforementioned processes, resulting in increased p38 activation and decreased JNK activation (48). Another previous in vitro study reported that in renal cell carcinoma, when using morphine at a dose of 2 nmol to 3.5 µmol in serum concentrations, converted to clinical dosage at 10-2,450 mg/day, it exerted no significant proliferative effects. However, after increasing the dose to 50 µmol in serum concentrations, which equated to a commonly used clinical dose of 35 mg, morphine promoted the migratory ability of renal cell carcinoma cells (49). Therefore, it is essential to carefully consider the pharmacokinetic and tolerance effects of morphine during its administration. A clinical trial on patients with cervical cancer have been previously performed assessing the effects of morphine combined with ketamine (morphine, 1 mg/kg/day; ketamine, 1 mg/kg/day) and morphine alone (1 mg/kg/day) for pain management, where both groups yielded a decrease in CD4+ and CD4+/CD8+ ratios. This was proposed to be achieved by modulating T cell activation and cytokine expression, specifically by inhibiting the secretion of IL-2, IFN-γ and IL-17, through the Janus kinase 3/STAT5 pathway (50).

Animal models of NSCLC have shown that morphine (0.1 µg/µl) can promote the proliferation, migration and invasion of H460 cell-induced NSCLC by activating the Src/PI3K/AKT/mTOR signaling pathway, inhibiting the G₂ phase of the cell cycle and suppressing apoptosis (51). Furthermore, another in vitro and in vivo study has demonstrated that, morphine (1.0 µmol/l) pre-treatment under hypoxic conditions can inhibit the production of the pro-angiogenic factor VEGF in Lewis lung carcinoma cells in vitro. In in vivo experiments, morphine exhibited an inhibitory effect on angiogenesis. This effect was mediated by morphine's interaction with hypoxia-inducible factor 1, which binds to its hypoxia response element, resulting in the suppression of VEGF production by µ receptor. Another murine study previously reported that morphine (plasma levels maintained between 250-400 ng/ml) can significantly reduce the blood vessel density, branching and length compared with those in the placebo group (52). This suggests that the MOR receptor-mediated processes can inhibit angiogenesis within the tumor microenvironment under certain conditions, thereby suppressing tumor growth. Morphine exhibit a dual effect on promote or inhibit tumor progression in different cancer models, including lung cancer model and breast cancer model, which may be due to the different downstream proteins activated by µ receptors on the surface of different cancer cells, the mechanism underlying the differences in performance among each cancer cell type warrants further exploration.

A previous study has addressed the δ receptor's role in breast cancer progression, with the majority primarily focusing on breast cancer. A mouse study previously indicated that δ receptor agonist (D-Ala²,D-Leu⁵)-Enkephalin treatment promoted lung metastasis by breast cancer cells, through the migratory Janus kinase 1/2-STAT3 axis and by enhancing epithelial-mesenchymal transition (53). Subsequent studies on human breast cancer cells have shown that expression of the δ receptor was increased in breast cancer cells, where the inhibition of the δ receptor was found to suppress cell proliferation, suggesting its role in the proliferation process (53,54). In addition, δ receptor was found to underly the progression of breast cancer by activating the protein kinase C/ERK signaling pathway. Therefore, the δ receptor inhibitors were proposed to serve as an adjunctive treatment for patients with breast cancer (53).

The role of the κ receptor in the tumor microenvironment primarily involved inhibiting angiogenesis, particularly the transformation of vascular progenitor cells into vascular endothelial cells. κ receptor agonists were found to inhibit VEGFR2 expression, thereby suppressing endothelial cell migration and angiogenesis in Lewis lung carcinoma and breast cancer (22,52,53).

Previous studies have shown that the κ receptor is highly expressed in endothelial progenitor cells and endothelial cells, where its activation can reduce the expression of VEGFR2 and neuropilin 1, which are necessary for angiogenesis, by decreasing cAMP production through inhibiting the cAMP/protein kinase A (PKA) pathway (22,52,53). In murine tumor models, κ receptor knockout mice exhibited enhanced tumor proliferation and angiogenesis following lung cancer cell transplantation compared with those in wild-type mice. Consequently, κ receptor agonists may inhibit tumor growth by suppressing angiogenesis (22,52,53).

The anti-angiogenic properties of κ receptor hold potential therapeutic value in cancer treatment. However, κ receptor agonists, such as butorphanol, nalbuphine and dynorphins, pose a risk of drug dependence and tolerance (55,56), necessitating careful consideration in their development and application, particularly for the combined treatment of cancer pain and anti-angiogenesis.

Additionally, another previous study on breast cancer cells found that the expression of κ receptor was significantly increased in breast cancer cells compared with that in non-tumor cells (normal human mammary epithelial cells). The inhibition of PI3K/AKT signaling by using inhibitors Recilisib and Buparlisib, or knockdown of the κ receptor, was found to reduce the viability and migration of breast cancer cells. These findings suggested that κ receptor may serve as a potential breast cancer growth antagonist (57).

Animal and cell studies have demonstrated that morphine can reduce the activity of T cells in mice by inhibiting the lymphocyte IL-2 production and IL-2 receptor expression in the spleen, which in turn reduces T cell activity and impairs immune function (32,59). In addition, cell experiments have demonstrated that morphine can reduce lactate dehydrogenase (LDH) release and the number of CD8+ T cells, whilst increasing the ratio of CD4+/CD8+ T cells (32,59). Another previous study on the effects of morphine on the anti-human immunodeficiency virus properties of CD8+ T cells has indicated that morphine can inhibit the activity of CD8+ T cells by directly binding to µ receptors, which can downregulate CD8+ T cell activity. In addition, morphine can reduce the secretion of IFN-γ by CD8+ T cells, thereby impairing their function. Morphine was also found to reduce the production of IFN-γ by CD8+ T cells and inhibits CD8 T cell-induced expression of the STAT1, further impairing IFN-γ signaling to compromise CD8 T cell activity, resulting in immune dysfunction.

Morphine can inhibit the macrophage-mediated clearance of pathogens (such as Streptococcus pneumoniae) by suppressing the toll-like receptor (TLR)9/NFκB signaling pathway, which increases the risk of infections (60). It can also reduce the production of IL-23 by dendritic cells and macrophages by inhibiting the TLR3 and nucleotide-binding oligomerization domain-containing protein 2 signaling pathways, weakening the body's defense mechanisms (60,61). In addition, recent studies suggest that morphine can significantly increase the expression of TLR4, p65, NF-κB and cytokines (IL-6 and TNF-α) in microglia and macrophages (62,63).

Numerous studies have demonstrated that morphine, as an opioid receptor agonist, can directly downregulate various phagocytic activity and enhance cell apoptosis in a number of cell types, including mouse peritoneal macrophages, bone marrowderived macrophage (BMDM) and peripheral blood monocytes (64,65). In particular, in BMDM, morphine can enhance LPS-induced macrophage apoptosis through a peroxisome proliferator-activated receptor γ-dependent mechanism (65). This interaction inhibits the production of ROS, including superoxide and peroxide, resulting in decreased superoxide anion production. Since these intermediates are involved in the bactericidal mechanism of phagocytes, morphine treatment resulted in decreased phagocytic efficacy and reduced macrophage bactericidal activity (40). Morphine has also been found to inhibit the formation of macrophage colonies in soft agar from cultured mouse bone marrow progenitors (34).

In rat models, the proliferation of NK cells was reported to be significantly suppressed in mice treated with morphine compared with that in controls. Administration of a nucleus accumbens shell blocker reversed the suppressive effects of morphine on the proliferation of NK cells in mice, suggesting that the nucleus accumbens serves a critical role in regulating peripheral immune responses. This process is likely mediated by the activation of sympathetic pathways and dopaminergic neurohumoral immunomodulation, with morphine indirectly affecting NK cells (34,66,67). A previous study demonstrated that morphine can inhibit lymphocyte proliferation and NK cell activity in vitro (68), whereas tramadol exhibits the opposite effects (67,68). This effect of tramadol was due to the (+)-enantiomer of tramadol inhibiting serotonin (5-HT) reuptake, increase extracellular 5-HT concentrations in the synaptic cleft, prolonging its combining time with 5-HT receptors and amplifying 5-HT signaling, which can promote immune activation, increase NK cell activity and IL-2 production (67). These findings suggest that different opioids may have distinct impact on the immune system.

Opioids are recognized for their inhibitory effects on immune cell function (12,34), including the suppression of lymphocytes, T cells and monocytes, which may in turn adversely affect the immune system and promote tumor growth. However, the literature also presents significant contradictions regarding these effects. These conflicting findings highlight the dual effects of opioids.

Dual role of µ receptors. µ receptor agonists may promote tumor growth under certain conditions. The activation of morphine-induced µ receptors can promote breast cancer cell proliferation both in vivo and in vitro (37,39). In addition, low concentrations of morphine in pancreatic cancer led to an increase in phosphorylated JNK, whilst the phosphorylation of p38 was reduced, resulting in an increment in tumor volume (48). However, morphine pre-treatment under hypoxic conditions inhibits VEGF production, which can suppress tumor growth (51,69). By inhibiting angiogenesis and production of M2-polarized macrophages, whilst inhibiting the production of MMP9 by macrophages, morphine can also suppress tumor growth (42,43).

Dual effect of κ receptors. Although κ receptor agonists can inhibit angiogenesis and tumor growth through the cAMP/PKA pathway, they may promote metastasis of breast cancer when activated in breast cancer cells (57,70).

The expression and functional profiles of different receptors, including µ and κ receptors, may vary in different types of tumors, leading to differences in anti-tumor or pro-tumor effects. The existing contradictory information are summarized in Table III.

Previous studies of opioid use in breast cancer have shown that the use of fentanyl, a δ receptor agonist, as anesthetics can reduce NK cell cytotoxicity compared with sevoflurane, during surgery. The use of δ receptor agonists in breast cancer can also promote the metastasis of breast cancer cells (53,71). However, activation of κ receptor has been documented to exhibit an inhibitory effect on estrogen receptor (ER)-positive breast cancer through the κ receptor/ER/X-box binding protein 1 pathway (72).

Opioids can inhibit lung cancer angiogenesis through different pathways. In Lewis lung carcinoma murine experiments, κ receptor knockout mice showed increased proliferation and enhanced tumor angiogenesis compared with those in wild-type mice, through the VEGF signaling pathway, indicating that κ receptor may inhibit the blood supply and growth of lung cancer (70). However, in lung cancer cell experiments, morphine may suppress the immune function by upregulating maelstrom spermatogenic transposon silencer (MAEL) expression, increasing the levels of Programmed death-ligand (PD-L)1, TGF-β and IL-10, whilst decreasing IL-2 levels (59).

Morphine, as a µ receptor agonist, can suppress the metastasis and growth of liver cancer cells by upregulating the expression of opioid growth factor receptor and downregulation of µ-opioid receptor and MMP-9 expression (73). Murine experiments have previously reported that tramadol can suppress the growth of orthotopic liver tumors by promoting M1 macrophage polarization in the tumor microenvironment (74).

As common analgesics in clinical settings, opioids have the potential to be combined with non-traditional cancer therapies. Emerging non-traditional cancer therapies, such as immunotherapy, primarily involve immune checkpoint inhibitors, adoptive cell therapy and cancer vaccines (86-88). Cancer immunotherapy is fundamentally based on the inhibition of immune escape mechanisms utilized by tumor cells. Currently, cancer immunotherapies primarily focus on immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (89). The application of PD-1 or its ligands, PD-L1 and PD-L2 monoclonal antibodies, selectively blocks the interaction between tumor cells and T cells. This restores antitumor immunity and enhances cytotoxic T cell-mediated tumor destruction, which ultimately causes tumor eradication (90). CTLA-4 monoclonal antibodies inhibit the co-stimulatory interaction between CTLA-4 molecules on regulatory T cells and Fc, which induces the death of regulatory T cells, reduces negative T cell regulation and enhances T cell-mediated immune responses (91). Immune checkpoint inhibitor therapy allows T cells to effectively infiltrate into tumor sites and form long-lasting immune responses by activating the body's T-cell immunity (87,92,93).

However, the modulation of immune activity, upregulation of T cell activity and reduction of Treg cell-mediated immunosuppressive activity can increase the risk of autoimmune complications and inflammation, such as checkpoint inhibitor pneumonitis induced by anti-PD-1/PDL-1 immune checkpoint inhibitors (94). To improve survival rates and quality of life, it is common to co-administer opioids and immunosuppressants to patients who commonly experience abdominal and lesion pain (94). Opioids can damage T cells and macrophages, where retrospective analyses of PD-1/PD-L1 concomitant medications have shown that patients with melanoma and NSCLC who receive opioids along with immunotherapy exhibit significantly lower overall survival rates, objective response rates and progression-free survival rates compared with patients who receive immunotherapy without opioids. This combination carries a higher risk of disease progression, gut microbiota dysbiosis and gut barrier dysfunction (95). Therefore, it is necessary to closely monitor changes in gastrointestinal function and inflammation markers when the treatment plan involves a combination of opioid administration and immunotherapy. Alternative treatments should be promptly adopted in the case of impaired gastrointestinal function.

Opioids can damage immune components, such as macrophages and T lymphocytes. However, considering the dose-dependent effects of opioids on the immune system, further studies are needed to explore how opioids can affect the tumor immune microenvironment, which differs from the normal immune composition (96). The long-term effects of opioids on the immune system and the complex immune system within the tumor microenvironment require further investigation.

It is necessary to develop individualized analgesic plans under the WHO pain management guidelines to minimize opioid dosages whilst ensuring effective pain relief. This requires further development and integration of non-opioid analgesics, adjuvant therapies and non-pharmacological interventions to reduce the dependence on opioids.

Regular assessments of pain intensity, functional capacity and possible opioid-associated side effects are essential, where treatment strategies must be modified as needed to achieve effective pain management whilst minimizing immune function disruption.

The specific pathways through which different opioid receptors influence immune cell function, angiogenesis and tumor progression need to be investigated to inform safer analgesic choices.

The interaction of opioids with immune checkpoint inhibitors and other immunotherapies should be examined to determine their impact on treatment efficacy and patient outcomes.

It is necessary to explore and develop novel pain management agents that provide effective analgesia with minimal immunosuppressive effects to preserve the integrity of cancer therapies.