Abstract LB416: Targeting XPO1 reprograms immune microenvironment and confers sensitivity to immune checkpoint blockade in pancreatic ductal adenocarcinoma

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Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that remains largely refractory to immune checkpoint blockade, owing to a profoundly immunosuppressive and immune excluded tumor microenvironment (TME). Nuclear cytoplasmic transport is essential for immune signaling in tumor and stroma. Exportin 1 (XPO1), the dominant nuclear export receptor, is overexpressed in PDAC and has been linked to therapeutic resistance, yet its role in PDAC immunopathogenesis has not been defined. Methods: In this study, we have utilized syngeneic and genetically engineered mouse models (GEMMs; KPC (Kras/p53/Cre)), digital spatial profiling (DSP; transcriptomics/proteomics), and single-nucleus RNA sequencing (snRNAseq). PDAC cells were treated with the selective XPO1 inhibitor Selinexor and Gemcitabine-nab-paclitaxel and profiled by bulk RNA sequencing. KPC tumors receiving Selinexor and Gemcitabine-nab-paclitaxel underwent snRNAseq, DSP, immunohistochemistry (IHC), and immune phenotyping. In Pan02 syngeneic model, Selinexor was combined with anti PD-1 antibody and tumor growth, and tumor and splenic immune subsets were quantified by flow cytometry. Results: Treatment of PDAC with Selinexor and Gemcitabine-nab-paclitaxel induced profound immune reprogramming characterized by broad remodeling of innate and adaptive immune responses. Our transcriptomics and flow cytometry analyses revealed enrichment of immune cells with anti-tumor immune function, antigen presentation and cytotoxic T cell activation. In line with these data, snRNAseq and IHC analysis of KPC tumors demonstrated increased intratumoral CD4+ and CD8+ T cell infiltration and elevated expression of T and B cell-associated transcripts (CD3d, CD3e, CD4, CD8a, CD8b1, CD19) together with upregulation of inflammatory monocyte marker Ly6C1, indicating coordinated expansion of effector lymphoid populations and anti-tumorigenic monocytes within a dense desmoplastic stroma. Furthermore, DSP showed that Selinexor and Gemcitabine-nab-paclitaxel enhanced pathways related to MHC class II-mediated antigen processing and leukocyte activation across both tumor and stromal compartments. Selinexor and Gemcitabine-nab-paclitaxel treatment suppressed the expression of the immunosuppressive chitinase-like protein Chil3, as this was validated by IHC, western blot and qPCR suggesting attenuation of pro-tumor myeloid signaling in PDAC TME. Consistently, Selinexor combined with anti-PD-1 therapy in Pan02 models significantly reduced tumor growth without much toxicity and reprogrammed myeloid cell populations toward Ly6ChiCd11b+ phenotype. Conclusions: Together, these data identify XPO1 driven nuclear export as a central upstream regulator of PDAC immune evasion and support clinical testing of XPO1 inhibitor immune checkpoint blockade combinations in pancreatic cancer. Ongoing validation in diverse preclinical models is informing planned clinical trials. Citation Format: Md Hafiz Uddin, Mohammed Najeeb Al Hallack, Misako Nagasaka, Sahar F. Bannoura, Husain Y. Khan, Amro Aboukameel, Fulya K. Alkan, Hilmi K. Alkan, Khalil Choucair, M Wasif Saif, Bin Bao, Ibrahim Azar, Eliza W. Beal, Miguel Tobon, Steve Kim, Amr Mohamed, Gregory Dyson, Rafic Beydoun, Ramzi M. Mohammad, Herbert Chen, Bassel El-Rayes F. El-Rayes, Philip A. Philip, Boris C. Pasche, Hasan Korkaya, Asfar S. Azmi. Targeting XPO1 reprograms immune microenvironment and confers sensitivity to immune checkpoint blockade in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB416.

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