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Background 80% of EOC are diagnosed in advanced stage (III/IV), and >60% of patients die within 5 years. 1 Neo/Adjuvant (N/ACT) peri-debulking surgery remains the SoC treatment, followed by maintenance PARPi for those non-progressing patients with HRD. Although immunotherapy is an attractive approach for the treatment of EOC due to its highly immunosuppressive (‘cold’) tumor environment (TME),2 the addition of immune checkpoint inhibitors to SoC has only modestly improved ORR with no survival benefit.3 IL-12 is a pleiotropic immuno-stimulatory cytokine with activity on the innate and adaptive immune systems and is able to turn ‘cold’ tumor microenvironments to ‘hot’. However, systemic treatment with IL-12 protein results in unacceptable clinical toxicity.The randomized controlled Phase I/II OVATION-2 study has shown that IMNN-001, an IL-12 gene-based nanoparticle delivered locally (intraperitoneally) limits systemic exposure and in combination with N/ACT is safe and improves PFS and OS by 3 and 13 months respectively, as compared with chemotherapy alone.3 Herein, we characterize the immune effects of IMNN-001 on patients’ TME.Methods Paired samples obtained pre-treatment at screening biopsy and post-IMNN-001 and NACT treatment at debulking surgery from patients with High Grade Serous Ovarian Cancer (HGSC) were analyzed for immune marker expression in tumor and TME by cyclic immunofluorescence analysis (Phenocycler-fusion) for the following markers: CD8, CD11c, CD44, CD4, HLA-DR, CD45, CD45RO, Ki67, CD14, CD3e, CD20, HLA-A, CD68, CD163, CD11b, CD16, Pan CK, FOXP3, PD-L1, PD-1, IDO-1. Cells in specimens segmented by a pathologist were quantified and normalized by tissue area.Results Of the six paired samples studied, two showed focal infiltration of predominantly CD4+ and CD8+ T cells (tertiary lymphoid nodules) and four showed diffuse immune infiltration post-treatment. Overall, trends of decreases in immune suppressive cells/mm 2 (M2 and g- and mMDSC) and increases in anti-tumoral M1 and myeloid DCs were identified. A favorable CD8/Treg ratio was also observed, along with a decrease in exhausted CD4+ and CD8+ cells in the TME. Further immunophenotypic analysis will be presented at the Congress.Conclusions IMNN-001induces T cell and myeloid cell mediated anti-tumoral responses across the heterogeneous TMEs characteristic of HGSC, likely driven by the multifaceted actions of IL-12 on both the innate and adaptive immune systems.The ability of IMNN-001 to generate IL-12, IFN-γ and TNF-α locally and the induction of a ‘hot’ TME collectively support the safety and efficacy observed in the OVATION-2 trial. A Phase III trial (OVATION-3, NCT06915025) is currently enrolling.Trial Registration NCT03393884References Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics. 2023 . CA Cancer J Clin. 2023 Jan;73(1):17–48.Blanc-Durand F, Clemence Wei Xian L, Tan DSP. Targeting the immune microenvironment for ovarian cancer therapy. Front Immunol. 2023 Dec 18;14.Thaker PH, Richardson DL, Hagemann AR, Holloway RW, Reed M, Bergman MK, Pothuri B, DePasquale S, Scalici JM, Bregar AJ, Darus CJ, Finkelstein K, Leath CA 3rd, Bell M, Warshal DP, Agajanian R, Indermaur MD, Mendivil AA, Provencher DM, Wei LJ, Borys N, Musso L, Lindborg SR, Faller DV, Anwer K, Bradley WH. OVATION-2: a randomized phase I/II study evaluating the safety and efficacy of IMNN-001 (IL-12 gene therapy) with neo/adjuvant chemotherapy in patients newly-diagnosed with advanced epithelial ovarian cancer. Gynecol Oncol. 2025 Jun;197:182–191.Ethics Approval This study as part of the translational research of the OVATION-2 trial was approved by all participant clinical sites’ Ethics Boards.