Pharmacologic wtIDH1 inhibition remodels the PDAC immune landscape and improves checkpoint blockade efficacy

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, with a five-year survival rate under 3%. Its aggressive biology, early metastasis, and profound resistance to therapy are driven in part by a dense, immunosuppressive tumor microenvironment (TME). Although metabolic inhibitors have shown promise in selecting molecular subtypes, the therapeutic potential of targeting metabolic vulnerabilities in wild-type tumors is less explored. Our earlier work identified that AG-120 (Ivosidenib), an FDA-approved inhibitor of mutant IDH1, also inhibits wild-type IDH1 (wtIDH1) under nutrient-restricted conditions typical of PDAC. Here, we investigate how wtIDH1 inhibition simultaneously disrupts tumor metabolism and reshapes the immune microenvironment. Methods: Miapaca-2, Panc-1, and KPC cells were cultured in low-glucose (2.5 mM) and low-magnesium (0.08 mM) media to simulate PDAC metabolic stress. Cell viability was measured using Titer-Glo, PicoGreen, and colony-formation assays. Cytoplasmic reactive oxygen species and mitochondrial ROS were quantified via DCFDA and MitoSOX using fluorescence and flow cytometry. Proliferation and cell-cycle regulation were evaluated by CellTrace and BrdU incorporation. Orthotopic and syngeneic mouse models were used to assess therapeutic efficacy, immune-cell infiltration, and synergy with anti-PD-1 therapy. Results: wtIDH1 inhibition significantly reduced cell proliferation, impaired DNA synthesis, and elevated mitochondrial and cytosolic ROS, leading to apoptosis. In vivo, Ivosidenib increased infiltration of CD45⁺ immune cells, including CD4⁺ and CD8+ central-memory T cells, and enhanced M1-like macrophage populations with reduced PD-L1 expression. Treatment group decreased M2-like monocytes and shifting the TME toward an inflammatory, anti-tumor state. Combination therapy with anti-PD-1 improved survival and conferred protection upon tumor rechallenge through robust central- and effector-memory T-cell expansion. Conclusion: wtIDH1 inhibition offers a dual benefit in PDAC by impairing tumor metabolism and promoting immune activation. This metabolic-immune reprogramming provides a strong rationale for combining wtIDH1 inhibitors with existing immunotherapies.