Natural compounds, including polysaccharides, alkaloids and polyphenols, have been shown to regulate immune responses within the tumor microenvironment (TME). These compounds achieve this by activating immune cells, inhibiting tumor cell proliferation, and promoting apoptosis. Furthermore, they modulate both immunosuppressive and immunoactivated states in the TME by influencing the activity of mast cells (MCs). MCs, as early and persistent infiltrating cells, play a pivotal role in allergic diseases and participate in various physiological and pathological processes. Their functions are primarily mediated through angiogenesis, tissue remodeling, and immunomodulation within the immune microenvironment. However, the role of MCs in tumorigenesis remains controversial. Depending on the tumor type, MCs exhibit remarkable plasticity and secrete a diverse array of signaling molecules that can significantly influence tumor progression. This review seeks to offer new insights into the role of MCs in tumorigenesis and development. Additionally, it explores the impact of natural compounds on the TME through MCs, contributing to a more comprehensive understanding of cancer therapy. Ultimately, this research aims to provide a scientific foundation for the development of novel tumor treatment strategies and to advance cancer therapy.