Ginsenoside derivative AD-1 suppresses colitis-associated colorectal cancer progression by reprogramming tumor-associated macrophage polarization via the AMPK/mTOR-glycolysis pathway.

Persistent inflammation plays a pivotal role in the development of colorectal cancer (CRC), and the incidence of colitis-associated colorectal cancer (CAC) continues to rise. Thus, exploring treatment strategies for CAC is critical for the prevention and management of CRC. Natural products derived from traditional Chinese medicine have recently gained attention for their therapeutic potential in cancer prevention. Here, we demonstrate that the ginsenoside derivative AD-1 significantly inhibits tumor progression in both AOM/DSS-induced CAC mice and CRC xenograft models. Moreover, AD-1 modulates tumor-associated macrophage (TAM) polarization both in vivo and in vitro. Specifically, AD-1 increases M1-like TAM polarization while suppressing M2 -like TAM in the spleens and colonic tissues of CAC mice, as well as in tumor tissues of CRC xenograft models. In vitro, AD-1 similarly promotes M1-like polarization and inhibits M2-like polarization in a TAM model established by co-culturing RAW264.7 cells with CT26 supernatant. Mechanistically, AD-1 activates AMPK signaling and inhibits mTOR activation, leading to enhanced glycolysis, which contributes to TAM metabolic reprogramming and polarization. Collectively, our study suggests that AD-1 represents a promising natural agent for modulating the tumor immune microenvironment and preventing the progression of inflammation-associated CRC.