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models. 1 This study investigates a novel combination of dual PTPN2/PTPN1 inhibition with a bispecific T cell engager to assess T cell activation and antitumor efficacy in patient-derived tumor model systems. Material and MethodsTwo patient-derived model systems were employed to assess the combinatorial effects of AC484 and an EpCAM/CD3 bispecific T cell engager tool compound (EpCAM/CD3).Precision-cut tumor slices (PCTS) were generated from freshly resected colorectal cancer tissue and treated ex vivo for 48 hours.In parallel, malignant pleural and ascitic effusions containing tumor cells, fibroblasts, and immune cells were collected and cryopreserved.Tumor cell lines established from these effusions were subsequently co-cultured with autologous effusion-derived cells in the presence of AC484 and EpCAM/CD3 for 72 hours.Immune activation and tumor cell cytotoxicity were quantified by flow cytometry, while PCTS were further analyzed by immunohistochemistry and multiplex cytokine profiling of culture supernatants.Results T cell activation (CD69) and reduced tumor proliferation (Ki67) induced by EpCAM/CD3 were further enhanced when combined with AC484 in PCTS.In malignant effusion co-cultures, single-agent treatment induced moderate tumor cell death, whereas combined treatment with EpCAM/CD3 and AC484 resulted in greater cytotoxicity.Consistent with these observations, multiplex cytokine profiling indicated a potentiated immune response in patient-derived models treated with the combination regimen.Conclusion Our findings demonstrate that the novel combination of dual PTPN2/PTPN1 inhibition with EpCAM/CD3 significantly enhances T cell activation and tumor cell killing in patient-derived PCTS and malignant effusion co-cultures.These results support further investigation of this combination as a promising approach to enhance antitumor immune responses.