AANG: A natural compound formulation for targeting macrophage-myofibroblast transition in non-small-cell lung carcinoma

Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). They are highly heterogeneous containing both anti-cancer and pro-tumor populations, which largely limits their translational development. Recently, we have identified macrophage-myofibroblast transition (MMT) as a novel and key origin of pro-tumoral CAF in non-small-cell lung cancer (NSCLC), targeting it with Traditional Chinese Medicine (TCM) may represent a safe and effective strategy for solid tumors. Here, by spatial single-cell bioinformatics, we revealed that not only Smad3 activation but also Smad7 reduction occurs in the macrophages undergoing MMT in clinical NSCLC. Therefore, we optimized our well-established TCM-derived natural product formulation AANG, which remodulated TGF-β1/Smad3/Smad7 signaling and synergistically blocked MMT on the bone marrow derived macrophages (BMDM) in vitro. More encouragingly, this optimized AANG can effectively block MMT-derived cancer progression on mouse cancer models with syngeneic lung cancer LLC and human NSCLC xenograft A549 without side-effect in vivo. Thus, AANG may represent the first natural compound formulation for blocking MMT-derived pro-tumoral CAF formation in the clinical NSCLC.