Abstract A116: Mito-Met10 remodels the pancreatic tumor microenvironment through MAVS activation and CD8+ T cell metabolic reprogramming
Maria Poimenidou, Mahmoud A. Eid, Janet Le, Elisabeth Solis, Donovan Drouillard, Chad Darnell, Donna McAllister, Michael B. DwinellAbstract
Introduction:
Pancreatic ductal adenocarcinoma is characterized by an immune-excluded tumor microenvironment that limits responsiveness to immunotherapy. Because mitochondrial metabolism regulates both tumor cell survival and immune cell function, mitochondria-targeted therapies may simultaneously induce tumor cell death and remodel anti-tumor immunity. We previously demonstrated that Mito-Met10, a mitochondria-targeted metformin analog, induces ER stress-mediated apoptosis in PDA. Here, we investigated whether Mito-Met10 also remodels the tumor immune microenvironment by promoting immune cell recruitment and T cell function.
Methods:
We treated orthotopic KPC PDA tumors with Mito-Met10 or vehicle and assessed immune cell infiltration and cytotoxic T cell activity by flow cytometry. Intratumoral cytokine and chemokine changes were profiled using an unbiased multiplex panel, with chemokine transcription confirmed in human PDA cells by qRT-PCR. To assess the mechanism linking mitochondrial stress to chemokine induction, we examined MAVS activation and NF-κB p65 phosphorylation, and correlated MAVS expression with survival in human PDA datasets. T cell metabolism and differentiation were evaluated by Seahorse flux analysis and flow cytometry in murine splenic T cells and in patient-derived T cells. We determined which immune populations were required for efficacy using antibody-mediated depletion of CD4+, CD8+, or NK1.1+ cells, and assessed tumor-infiltrating lymphocyte function in ex vivo co-culture killing assays.
Results:
Mito-Met10 significantly reduced orthotopic tumor burden while increasing CD45+ immune infiltration and Granzyme B+ CD8+ T cells. Mito-Met10 induced MAVS oligomerization and NF-κB p65 phosphorylation in tumor cells, and elevated MAVS expression was associated with improved survival in human PDA datasets. Consistent with MAVS activation, multiplex profiling revealed robust induction of the T cell-recruiting chemokines CXCL9 and CCL5, together with IL-7, IL-15, IL-12p70, IFNγ, IFNβ, IL-6, and IL-18; increased CXCL9 and CCL5 transcription was confirmed by qRT-PCR in human PDA cells. Building on our previous findings that Mito-Met10 enhances T cell proliferation and activation, Mito-Met10 reduced oxidative phosphorylation in CD4+ T cells while selectively increasing glycolysis in CD8+ T cells. In patient-derived T cells, Mito-Met10 also promoted a dose-dependent expansion of central memory CD8+ T cells. Importantly, depletion of CD8+ T cells, but not CD4+ or NK1.1+ cells, abolished the anti-tumor efficacy of Mito-Met10, and TILs isolated from treated tumors exhibited significantly greater ex vivo cytotoxic activity.
Conclusions:
Together, these data suggest that Mito-Met10 remodels the PDA TME from an immune-excluded to an immune-permissive state through tumor-intrinsic MAVS activation and enhanced CD8+ T cell metabolic fitness and cytotoxic function, supporting mitochondrial metabolic targeting as a strategy to sensitize PDA to T cell-based immunotherapy.
Citation Format:
Maria Poimenidou, Mahmoud A. Eid, Janet Le, Elisabeth Solis, Donovan Drouillard, Chad Darnell, Donna McAllister, Michael B. Dwinell. Mito-Met10 remodels the pancreatic tumor microenvironment through MAVS activation and CD8+ T cell metabolic reprogramming [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A116.