The new revolution of immunotherapy: is it time to pair it with the old one? —Yellow Leader as a candidate

With the advent of immunotherapy in cancer treatment, the natural history of this disease has changed. The immune checkpoint therapies have shown great promise in this setting, by potentiating the body’s natural immune response against tumor cells. Checkpoint inhibitors (CPIs) have definitively consolidated the target of reversing the immunoevasion as one of the most universal strategies to change the natural evolution of advanced oncological diseases, and to maximize CPI treatment efficacy, synergies in immune system modulation must be seriously considered. In the field of Integrative Oncology, Chinese medicinal mushrooms have been increasingly promoted as excellent anticancer immunoenhancers. However, many plants of traditional Chinese medicine have been less visible, but—as scientific literature reveals—not less powerful as antitumor immunomodulators. Astragalus membranaceous root is a venerated plant as a tonic in traditional Chinese pharmacopoeia. This is known to be beneficial to relieve mild disorders and to help in more serious diseases, such as cancer. For this great restorative capacity was why it won the name of Huang Qi, “leader of all tonics”, or Yellow Leader, because of its colour. Astragalus root contains a variety of immunoactive constituents. Its power as an antitumor root is not only due to its immunomodulatory activity; it is able to modulate several apoptotic and antiangiogenic signaling pathways and interact with specific transcription molecules. We propose a rational model of the combination of CPI with Astragalus root chosen as representative of traditional immunotherapy, to set a paradigmatic frame to develop novel target-specific combinations with natural immunomodulators. We are convinced that by combining these two strategies in immunotherapy—the new one and the old one—we can definitely overcome immune cell exhaustion, boost the response to immunocheckpoint treatment, and minimize side effects, to get better and more efficient results in cancer immunotherapy.