Ketamine Beyond Anaesthesia: Analgesic, Psychiatric, Antitumour, and Immunomodulatory Actions and Their Signalling Mechanisms.

PURPOSE OF REVIEW: To synthesize current evidence on ketamine for cancer-related pain and its intersecting psychiatric, anti-tumor, and immunomodulatory actions, emphasizing mechanisms, clinical relevance, and uncertainties relevant to oncology.

RECENT FINDINGS: Ketamine provides analgesia primarily through non-competitive antagonism of N-methyl-D-aspartate receptors and additional effects on excitatory, inhibitory, and opioid-related signaling. In patients with refractory cancer pain, it may be a useful adjunct to opioid-based multimodal analgesia and may reduce opioid requirements; however, clinical evidence remains limited and heterogeneous. Its rapid antidepressant effects may be relevant to the reciprocal burden of pain and depressive symptoms in cancer. Preclinical studies report antiproliferative, pro-apoptotic, and ferroptosis-associated effects across several tumor models, involving phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin, extracellular signal-regulated kinase, and non-coding RNA-associated pathways. These findings are not uniform: breast cancer models have suggested potentially pro-metastatic effects. Immune effects are likewise dose-, context-, and perioperative-setting dependent, with reports of anti-inflammatory, immunosuppressive, and neutral effects. Ketamine is a potentially valuable opioid-sparing adjunct for selected patients with cancer-related pain and may also address comorbid depressive symptoms. Its putative direct anti-tumor and immunomodulatory actions remain predominantly preclinical and context dependent and should not currently guide oncologic treatment decisions. Appropriately powered clinical studies should define patient selection, dose and route, duration, safety, immune consequences, and long-term oncologic outcomes.