SMAD4 and cancer: Then, complexes between phosphorylated Smad2/3 and Smad4 are formed and translocated into the nucleus to bind with the associated DNA strands and disrupt their transcription, thereby undermining the activation of fibroblasts (cancer associated fibroblasts, namely CAF) in TME, which typically involves the up-regulation of markers such as α-SMA [25, 46].