Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer

Cross-talk between the tumor microenvironment (TME) and cancer cells plays an important role in acquired drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The role of tumor-associated macrophages (TAMs), the major component of the TME, in acquired resistance remains unclear. In this study, M2-like reprogramming of TAMs and reduced phagocytosis by macrophages were observed in gefitinib-resistant lung cancer cells and tumor xenografts. CD47 was upregulated in TKI-resistant lung cancer cells, and M2 macrophage polarization and cancer cell escape from macrophage phagocytosis were enhanced. Culture medium from TKI-resistant cells led to metabolic reprogramming of TAMs. STAT3 was associated with CD47 expression in TKI-resistant lung cancer cells. Genetic and pharmacological inhibition of STAT3 enhanced the phagocytic activity of TAMs and alleviated the acquired resistance to EGFR-TKIs via inhibiting the CD47-SIRPα signaling axis and M2 polarization in the co-culture system. Moreover, STAT3 transcriptionally regulated CD47 expression by binding to consensus DNA response elements in the intron of the CD47 gene. Furthermore, the combination of gefitinib with a STAT3 inhibitor and an anti-CD47 monoclonal antibody alleviated the acquired resistance to gefitinib in vitro and in vivo. Collectively, our study reveals the role of TAM reprogramming and the CD47-SIRPα axis in acquired EGFR-TKI resistance and provides a novel therapeutic strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer. Graphic Abstract: M2-like reprogramming of TAMs and reduced phagocytosis of macrophage play an important role in TKI acquired resistance. Combination of STAT3 inhibitor, αCD47 mAb and gefitinib to target the CD47-SIRPα axis and TAM provides a new strategy to overcome TKI acquired resistance. [Display omitted] •M2-like reprogramming of TAMs and reduced phagocytosis by macrophage were found in gefitinib-resistant lung cancer cells and tumor xenografts.•Genetic and pharmacological inhibition of STAT3 enhances the phagocytic capacity of TAMs and alleviates the acquired resistance to EGFR-TKIs via inhibiting CD47-SIRPα signaling axis and M2 polarization in co-culture system.•STAT3 transcriptionally regulates CD47 expression through binding to consensus DNA response elements in the promoter and intron regions of the CD47 gene.•The combination of STAT3 inhibitor and anti-CD47 mAb alleviates the TKI acquired drug resistance in vitro a