When SMAD4 is inactivated, the classical SMAD2/3/4‐mediated pathway is impaired, causing TGF‐β signaling to shift toward noncanonical routes such as MAPK, PI3K/AKT, JNK, and Rho–GTPase pathways; these alternative pathways can drive hallmark malignant features, including EMT, tumor cell invasion, immunosuppression, and angiogenesis. Here, SMAD2 is linked to neoplasm.