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Background Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. Methods Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. Results Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. Conclusion PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.