Patients　with　gallbladder　carcinoma　(GBC)　lack　effective　treatment　methods　largely　due　to　the　inadequacy　of　both　molecular　characterisation　and　potential　therapeutic　targets.　We　previously　uncovered　a　spectrum　of　genomic　alterations　and　identified　recurrent　mutations　in　the　ErbB　pathway　in　GBC.　Here,　we　aimed　to　study　recurrent　mutations　of　genes　and　pathways　in　a　larger　cohort　of　patients　with　GBC　and　investigate　the　potential　mechanisms　and　clinical　significance　of　these　mutations.We　performed　whole-exome　sequencing　(WES)　in　157　patients　with　GBC.　Functional　experiments　were　applied　in　GBC　cell　lines　to　explore　the　oncogenic　roles　of　＜i＞ERBB2＜/i＞/＜i＞ERBB3＜/i＞　hotspot　mutations,　their　correlation　with　PD-L1　expression　and　the　underlying　mechanisms.　ERBB　inhibitors　and　a　PD-L1　blocker　were　used　to　evaluate　the　anticancer　activities　in　co-culture　systems　in　vitro　and　in　vivo.WES　identified　＜i＞ERBB2＜/i＞　and　＜i＞ERBB3＜/i＞　mutations　at　a　frequency　of　7%-8%　in　the　expanded　cohort,　and　patients　with　＜i＞ERBB2＜/i＞/＜i＞ERBB3＜/i＞　mutations　exhibited　poorer　prognoses.　A　set　of　in　vitro　and　in　vivo　experiments　revealed　increased　proliferation/migration　on　＜i＞ERBB2＜/i＞/＜i＞ERBB3＜/i＞　mutation.　Ectopic　expression　of　ERBB2/ERBB3　mutants　upregulated　PD-L1　expression　in　GBC　cells,　effectively　suppressed　normal　T-cell-mediated　cytotoxicity　in　vitro　through　activation　of　the　PI3K/Akt　signalling　pathway　and　contributed　to　the　growth　and　progression　of　GBC　in　vivo.　Treatment　with　an　ERBB2/ERBB3　inhibitor　or　a　PD-L1　monoclonal　antibody　reversed　these　immunosuppressive　effects,　and　combined　therapy　revealed　promising　therapeutic　activities.＜i＞ERBB2＜/i＞/＜i＞ERBB3＜/i＞　mutations　may　serve　as　useful　biomarkers　in　identifying　patients　who　are　sensitive　to　ERBB2/ERBB3　inhibitors　and　PD-L1　monoclonal　antibody　treatment.NCT02442414;Pre-results.