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Immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in patients with advanced malignancies. However, their association with immune thrombocytopenia (ITP) poses a critical risk of severe hemorrhage and necessitates treatment discontinuation. The precise molecular mechanisms underlying ICI-associated ITP remain largely unclear, critically impeding the development of predictive biomarkers and targeted therapeutic strategies. Here, we present a case report of an elderly patient with stage IV gastric adenocarcinoma who developed recurrent ITP following programmed death receptor-1 (PD-1) inhibitor serplulimab, trastuzumab and chemotherapy. Notably, longitudinal peripheral blood mononuclear cell samples were collected and subjected to transcriptomic profiling before and after two distinct ITP episodes: the initial occurrence and a recurrence triggered by PD-1 inhibitor rechallenge, providing matched time-resolved data for mechanistic analysis. Our findings demonstrate that ICIs-induced ITP involves a dual pathogenic mechanism combining immune-mediated platelet destruction and intrinsic megakaryopoietic impairment providing a novel conceptual framework for understanding this immunotherapy complication. And this represents the first prospective longitudinal investigation combining serial biospecimen collection with transcriptomic profiling (RNA sequencing) to elucidate mechanisms underlying ICIs-induced ITP.