Objective:　The　combination　of　epithelial　growth　factor　receptor　tyrosine　kinase　inhibitors　(EGFR-TKIs)　and　immune　checkpoint　inhibitors　(ICIs)　leads　to　an　increased　incidence　of　severe　immune-related　adverse　events　(irAEs).　However,　the　mechanisms　underlying　macrophages　in　irAEs　have　not　been　elucidated.　Methods:　An　osimertinib　and　ICI-induced　irAE　mouse　model　was　constructed.　Lung　micro-CT　scans　were　used　to　assess　the　degree　of　inflammatory　infiltration.　Hematoxylin-eosin　staining　was　used　to　analyze　the　histopathologic　inflammatory　infiltration　in　mouse　liver　and　lung　tissues.　Flow　cytometry　was　used　to　detect　the　percentages　of　T　cells,　NK　cells,　and　macrophages　and　the　expression　of　EGFR.　Enzyme-linked　immunosorbent　assay　(ELISA)　was　used　to　detect　the　serum　interleukin　(IL)-6,　alanine　transaminase　(ALT),　ferritin,　and　tumor　necrosis　factor　(TNF)-alpha　levels.　Total　RNA　extracted　from　mouse　liver　macrophages　was　analyzed　by　RNA-seq.　Simple　Western　blot　analysis　was　used　to　detect　the　IL-6/JAK/STAT3　pathway　activation　state.　Results:　Osimertinib　combined　with　ICIs　upregulated　EGFR　expression　on　macrophages　with　increased　serum　IL-6,　ALT,　and　ferritin　levels.　RNA-seq　and　simple　Western　blot　analysis　of　mouse　liver　macrophages　confirmed　that　that　the　IL-6/JAK/STAT3　pathway　was　activated　in　the　combination　treatment　group.　Ruxolitinib　blocked　the　IL-6/JAK/STAT3　pathway　and　significantly　decreased　the　serum　IL-6,　ALT,　and　ferritin　levels　in　the　combination　treatment　group.　Conclusions:　An　osimertinib　and　ICI-induced　irAE　mouse　model　was　constructed　that　showed　osimertinib　combined　with　ICIs　inhibited　EGFR　phosphorylation　and　activated　the　IL-6/JAK/STAT3　signaling　pathway　in　mouse　liver　macrophages,　which　led　to　the　release　of　relevant　cytokines.