Conclusion
By targeting TREM2 and activating the STING signaling pathway in TAMs, prodrug GB2 exhibits excellent anti-tumor efficacy and immune-activating capacity in the mouse colon cancer model.
Results
Over-expressed TREM2 in TAMs correlates with CRC progression. Via targeting TREM2 expressed in TAMs, GB2 induces comprehensive tumor regression by administrating intravenously in mouse colon cancer models, as well as in a STINGlow mouse melanoma model, with no systemic toxicity. Upon treatment with GB2, TAMs exhibit an M1 phenotype with pro-inflammatory function and demonstrate enhanced phagocytosis capacity. The molecular mechanisms involve (1) GB2 upregulating the Glycolysis-ROS-HIF-1α axis, thereby promoting glucose metabolism and inflammatory cytokine expression; (2) GB2 inducing endoplasmic reticulum-mitochondria contact (MERC), leading to mitochondrial fission, ultimately facilitating Ca2+-mediated phagocytosis. Besides, GB2-treated macrophages reverse immunosuppression, facilitating CD8+ T cell tumor infiltration and effector function. Combining GB2 with αPD-1 therapy reveals a synergistic effect on tumor inhibition, leading to prolonged mouse survival.