Targeting tumor-associated macrophages through phytochemicals: a promising strategy for cold tumor therapy

Abstract Immunotherapy serves as the fourth modality for cancer treatment, following surgery, radiotherapy, and chemotherapy. However, its efficacy remains inconsistent due to the heterogeneity of the tumor microenvironment (TME). Tumors characterized by an immunosuppressive TME that are unresponsive to immunotherapy are termed “cold tumors.” Thus, strategies to reverse this immunosuppressive environment are promising for treating cold tumors. Tumor-associated macrophages (TAMs) play a significant role in this process, making TAM-targeting therapies potentially valuable. Natural products (NPs), which are bioactive compounds from traditional herbs, exhibit broad anticancer effects and modulate TAM polarization, positioning them as a promising source for anticancer agents. This article explores the relationship between TAMs and the TME, emphasizing the mechanisms by which natural products, such as terpenoids and quinones, influence TAM polarization to inhibit tumor progression. By analyzing TAM roles in the TME and summarizing existing natural products targeting TAM polarization, this study offers insights for developing novel TAM-targeting drugs, and aids in the conversion of cold tumors to hot tumors. Graphical Abstract