Work

944 Succinate-based metabolic reprogramming of innate and adaptive immunity for ovarian cancer immunotherapy

Year: 2026

Type: conference-abstract

Abstract: Background The efficacy of adoptive cell therapies in solid tumors remains limited by the immunosuppressive tumor microenvironment (TME). High metabolic activity of cancer cells depletes nutrients and generates acidic byproducts that partly contributes to blunted T cell directed antitumor immunity. Macrophages offer unique advantages in solid tumors through their ability to infiltrate tissues and phagocytose tumor cells, and CAR-engineered macrophages (CAR-Ms) have shown promise in preclinical studies. However, macrophages are often reprogrammed into tumor-promoting M2-like tumor-associated macrophages within the TME, limiting therapeutic efficacy. Succinate, a tricarboxylic acid (TCA) cycle intermediate, has emerged as a regulator of immune cell activation, but its therapeutic potential across innate and adaptive immune cells remains incompletely understood. We investigated whether sustained intracellular delivery of succinate using polymeric formulations could enhance the antitumor activity of both macrophages and CD8 T cells.Methods Polyethylene succinate (PES) nanoparticles and pABS polymers were synthesized and characterized for size, polydispersity, and zeta potential. Mesothelin-targeting CAR-Ms were generated from mouse bone marrow-derived macrophages and human monocyte-derived macrophages. CD8 T cells from OT-I transgenic mice were expanded in the presence of succinate polymers or control treatments. Cellular metabolism was assessed by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Phenotypic and functional analyses included flow cytometry, cytokine profiling, cytotoxicity, and phagocytosis assays. Antitumor efficacy of succinate-treated T cells was evaluated in murine ovarian cancer and melanoma models.Results Succinate polymers enhanced metabolic activity in both macrophages and CD8 T cells. PES-treated CAR-Ms exhibited increased ECAR and OCR, elevated expression of M1-associated markers, increased transcription of IL-6, TNFα, and IL-1β, and reduced anti-inflammatory programs. Succinate treatment reversed IL-4-induced M2-like polarization and enhanced phagocytosis of mesothelin-expressing ovarian cancer cells. In parallel, succinate-treated CD8 T cells demonstrated enhanced metabolic fitness, increased IFNγ and Granzyme B production, and improved cytotoxicity against ovarian cancer cells. These effects were maintained under lactate-rich conditions that mimic the suppressive TME. In vivo, adoptive transfer of succinate-treated T cells reduced tumor burden, improved survival, and increased intratumoral accumulation of cytotoxic T cells compared with untreated or dimethyl succinate-treated controls.Conclusions Sustained intracellular delivery of succinate enhances both innate and adaptive antitumor immunity by metabolically reprogramming macrophages and CD8 T cells. These findings support succinate-based metabolic engineering as a promising strategy to improve cellular immunotherapies for ovarian cancer.Ethics Approval All animal experiments were performed in accordance with protocols approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC).

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0944