As a class of immune checkpoint inhibitors (ICIs), programmed cell death protein-1 (PD-1) blockade have demonstrated remarkable efficacy in the treatment of various malignancies. However, their clinical application is constrained by the high incidence of immune-related adverse events (irAEs), which arise from nonspecific immune activation and can affect multiple organ systems, with severe cases posing life-threatening risks. This study integrated high-throughput proteomic and metabolomic analyses to systematically characterize the molecular features associated with irAEs in cancer patients receiving PD-1 inhibitor therapy. The results showed that, following the first treatment, patients who developed irAEs exhibited activation of the NF-κB pathway, along with lower baseline levels of SNRPA and higher expression of CD63. Metabolomic analyses further revealed that the kynurenine/tryptophan ratio was significantly elevated in the irAE group both at baseline and post-treatment compared with patients who did not develop irAEs. In addition, significant differences in the abundance of specific lipids were observed between the two groups prior to the administration of immunotherapy. Our findings systematically elucidates the immune response triggered by PD-1 blockade treatment, providing useful insights for the potential early identification and risk stratification of irAEs in cancer patients undergoing PD-1 blockade therapy.