Echinacea’s Power: Boosting Anti-Tumor Immunity with EPPA

The tumor microenvironment, which is made up of blood vessels, immune cells, fibroblasts, inflammatory cells generated from bone marrow, different signaling chemicals and extracellular matrix, is a complex ecosystem that surrounds the tumor site. The components of the microenvironment interact with each other and with the tumor to enable cancer to grow. The tumor microenvironment gives a tumor all of the nutrients it needs and makes space for the tumor to expand. Macrophages are the most abundant immune cells in the tumor microenvironment and play a central regulatory role. Macrophages infiltrating tumor microenvironment are defined as tumor-associated macrophages (TAMs), accounting for approximately 30–50% of total immune cell counts.  Typically, high macrophage infiltration is associated with poor patient prognosis in many types of cancer, such as breast, lung, and gastric cancers.

Over the last decade cancer treatment has undergone a revolution. Traditionally, chemotherapy drugs targeted tumors more broadly; but now, new therapeutic strategies target specific cells within the tumor microenvironment. For instance, TAMs have been proven to be related to the occurrence, development, angiogenesis, and metastasis of tumors, suggesting that TAMs could be a potential therapeutic target and prognostic biomarker for tumors. Current antitumor strategies targeting TAMs include inhibiting the recruitment of macrophages, promoting TAMs depletion, regulating its polarization, and enhancing TAM phagocytosis. Targeting TAMs has become one of the main anti-tumor therapeutic strategies in personalized medicine. Immunotherapy has shown remarkable promise in the treatment of cancer, with immune checkpoint inhibitors like CTLA-4 and PD-1/PD-L1-based therapies significantly impacting tumor microenvironment and immune cell functions. However, a significant proportion of patients do not benefit from these treatments, either due to the development of immunotherapy resistance or the occurrence of severe side effects. This creates an urgent need for approaches that can modulate the tumor microenvironment to enhance anti-tumor immunity and reduce immune evasion. Moreover, given many targets of TAMs still have not been discovered, or suitable targeted drugs have not yet been developed, it will be necessary to further study the molecular mechanism of the interaction between tumor cells and TAMs to find more effective new targets and drugs.

Natural products have gained increasing attention in cancer therapy. Echinacea purpurea, a medicinal plant commonly used in Europe and North America for upper respiratory tract infections, has exhibited various pharmacological activities, including immunomodulation, anti-fungal, antibacterial properties, and antioxidant effects. These activities are attributed to its bioactive constituents, such as alkamides, caffeic acid derivatives, and polysaccharides. However, variations in extraction methods and solvents used can lead to differences in the chemical profile and biological activity of Echinacea preparations, making it important to understand the specific roles of its constituents and derivatives. Current research on Echinacea’s medicinal applications has been primarily focused on its immunomodulatory effects, particularly the strong adjuvant effects of Echinacea polysaccharides on T cell responses. Nonetheless, the exact constituents responsible for these immune activities, especially in the context of anti-tumor immunity, remain unclear.

In a new study published in the Innovation Journal, led by Professor Hong Wu and colleagues from the State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources at the South China Agricultural University investigated the role of natural products, specifically Echinacea purpurea polysaccharides (EPPA), in cancer immunotherapy. Their research provides new insights into the modulation of the tumor microenvironment and immune cells, particularly macrophages, which are essential components of anti-tumor immunity.

The research team isolated and purified a homogeneous polysaccharide from E. purpurea, EPPA, and conducted experiments using H22 ascites tumor-bearing and orthotopic colorectal cancer mouse models to evaluate the anti-tumor activity of EPPA. Their findings revealed that oral administration of EPPA effectively inhibited tumor growth in mice while promoting the polarization of M1 macrophages, a subtype of macrophages associated with anti-tumor immunity. The authors showed that EPPA enhanced the production of interleukin-1β in M1 macrophages by activating the cellular inflammasome and reprogramming the transcriptomic and metabolic profiles of these macrophages. Hence, the potential of EPPA supplementation as an adjuvant therapy for tumors by targeting M1 macrophages, thereby enhancing anti-tumor immunity. The researchers conducted a thorough analysis of EPPA’s chemical structure, showing that it is an arabinogalactan primarily composed of L-Ara, D-Gal, and D-GalA. This understanding of EPPA’s structure is essential for further research and biomedical applications. Importantly, their work expands our understanding of the complex interactions within the tumor microenvironment and how natural products like EPPA can be harnessed to modulate immune responses, particularly within the context of cancer immunotherapy.

The researchers also highlighted the importance of natural products in combination with conventional treatments to enhance the body’s immune response and improve treatment outcomes. This approach aligns with the broader trend in medicine toward more personalized and targeted therapies that consider the individual patient’s immune status and the specific characteristics of their tumor microenvironment. In conclusion, Professor Hong Wu and colleagues have demonstrated EPPA effects on the tumor microenvironment and showcase the potential within natural products and studying their mechanisms of action and clinical applications in cancer treatment.