Research progress on the impact of opioids on the tumor immune microenvironment (Review).

Opioids have been extensively used in cancer pain management because they can significantly improve the quality of life of patients with advanced cancer. However, recent evidence suggests that opioids can also modulate the tumor immune microenvironment by interacting with opioid receptors on immune cells, potentially regulating tumor progression and efficacy of cancer treatments. Notably, morphine can exhibit a dose-dependent effect on tumor immunity in pancreatic cancer and renal cell models, with lower doses potentially promoting tumor migration and invasion of pancreatic cancer cells, whereas higher doses shows the effect of inhibiting migration and invasion through distinct molecular pathways. The present review therefore comprehensively explored the mechanisms by which opioids can regulate the tumor immune microenvironment, focusing on their effects on immune cells, oxidative stress and angiogenesis. It also examined the interactions between opioids and other analgesics, along with their potential impact on immune modulation. All relevant articles and materials were retrieved from PubMed using the key words 'opioids', 'immune system', 'T cells', 'monocytes', 'macrophages', 'lymphocytes', 'natural killer cell', 'immunotherapy', 'immune cell function' and 'dose dependent effect'. The immunosuppressive effects of opioids, particularly through the µ-opioid receptor, can suppress the activity of natural killer cells, impair antigen presentation and promote the function of regulatory T cells (Tregs). These effects may contribute to tumor progression and metastasis. The severity of these immunosuppressive effects appears to be dose-dependent and can vary among different tumor types. There is evidence to suggest that tumors with higher immune responsiveness will experience more pronounced suppression, including the reduction of tumor angiogenesis, resulting in a decrease in tumor volume and decrease in tumor metastases. Furthermore, the combination of opioids with other analgesics, such as non-steroidal anti-inflammatory drugs, has the potential to exacerbate immunosuppression, which can in turn increase the risk of infections. Therefore, although opioids are essential for pain management in patients with cancer, their potential to modulate the immune microenvironment and promote tumor progression requires careful consideration. Clinicians should evaluate the advantages and disadvantages of opioids, especially regarding emerging immunotherapies, to minimize their potential negative effects on the outcomes of cancer treatments. Future studies are recommended to prioritize the development of strategies that optimize pain management whilst preserving immune function, such as receptor-specific opioid formulations or adjunctive therapies targeting immunosuppressive pathways.