In summary, our study is the first to illustrate the crucial roles of SH2B3 in lung cancer and reveals that TGF-β1/SH2B3 axis regulates the anoikis resistance and EMT process of lung cancer cells via JAK2/STAT3 and SHP2/Grb2/PI3K/AKT signaling pathways. Here, TGFB1 is linked to lung cancer.