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In TGF--driven NSCLC models, loss of Smad3 disrupts SMAD3/SMAD4 complex formation, suppresses Snail expression, and attenuates ECM accumulation, thereby reducing EMT and fibrosis ( Beyond Smad signaling, EMT is regulated by non-Smad pathways including MAPK (ERK, JNK, p38), PI3K/AKT, and Rho-GTPases ( 2.2 Inflammatory and tumor microenvironment (TME) Recent reviews and experimental studies have demonstrated that signaling from the tumor microenvironment actively drives EMT, thereby promoting tumor cell invasion and metastasis ( Within the TME, tumor-associated macrophages (TAMs) are highly plastic immune cells that can differentiate into either classical M1 or alternative M2 phenotypes