A total of 1871 proteins were identified by iTRAQ and bioinformatics analysis, among which 119 differentially expressed proteins (P<0.05), including 74 up-regulated proteins and 45 down-regulated proteins. And 37 immune-related proteins were screened, including 19 up-regulated proteins and 18 down-regulated proteins, which are mainly enriched in Notch, Hippo, NF-κB, TGF-β and some other signaling pathways which related to the immunoglobulin, wound healing and inflammation. Up-regulated proteins such as MRC1 LBP, EPX, FCGBP, and down-regulated proteins like CD109, CNN3, NOTCH3, LAMB2 had the similar trend as the mRNA expression level in tissues 5, 20, 50,90 days after inserting. It is speculated that in the process of pearl sac formation, molluscs may protect cells from the damage by immune mechanism and inflammation through these differential proteins, and promote the fusion of pearl sac and outer mantle. This study provided basic data for understanding the immune response caused by Hyriopsis cumingii nucleus insertion.