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The last 20 years of research in the field of chronic cancer pain, have expunged the well-established idea that chronic cancer pain is ‘unique’.Immunology has definitely clarified that neuroinflammation, namely a persistent inflammatory response elicited by a variety of different stressors, is mediated by nociceptors expressed by peripheral and central nervous system fibers (high speed warning) and by innate and adaptive immune cells (defense and adaptation). Neuroinflammation is thus become the unifying paradigm of all chronic painful diseases including cancer pain that goes out the window of symptoms and enters the door of diseases.The complexity of tumor microenvironment consisting of a myriad of cells beyond tumor cells, including fibroblasts and stromal cells, endothelial cells, immune myeloid and lymphoid cells, resident and newly formed nervous fibers, and extracellular matrix, is the key driver determining the quality and intensity of cancer pain. Such complexity is regulated by a wide array of soluble mediators (cytokines, neuropeptides, neurotransmitters, lipids, opiates, etc.) and their receptors. This milieu exerts both direct effects on tumor growth and progression, and on intratumoral inflammatory/immune responses, and acts at distance on pain (threshold and response), normal and abnormal response to opioids (analgesia and hyperalgesia), fever, depression, and cognitive disorders. The main words of the crosstalk between tumor, immune and central nervous systems (neuroimmune activation) are the cytokines, and this activation might represent an important therapeutic target for global palliative cancer care.