Our research demonstrated the following results: (1) Trop2 up-regulated IGF2 level and promoted the development of gefitinib drug resistance in NSCLC by binding IGF2R; (2) Trop2 binding with IGF2R activated IGF2-IGF1R-Akt signaling to re-construct the TME and induced gefitinib resistance in NSCLC. Here, IGF1R is linked to non-small cell lung carcinoma.