Elucidation of targetable mechanisms sustaining immunosuppressive neutrophils in the brain tumor microenvironment

Glioblastoma (GBM), the most aggressive and lethal form of brain cancer in adults, is highly resistant to promising immunotherapies, largely due to a myeloid cell-driven immunosuppressive microenvironment (TME). The emerging key contribution of neutrophils to this immunosuppressive milieu that restricts anti- cancer immunity, therefore promoting tumor growth and resistance to immunotherapies, has sparked interest in therapeutically targeting these cells in brain tumors. Despite recent advances in understanding the phenotypic and functional heterogeneity of neutrophils in tumor beds, there are no effective approaches to specifically target immunosuppressive subsets. Thus, the goal of this study is to dissect targetable tumor- driven mechanisms sustaining pro-tumoral and immunosuppressive neutrophils in the TME; as this knowledge is the key to developing impactful, new, and selective neutrophil-targeting therapies to unleash anti-tumor immunity and sensitize resistant tumors, like GBM, to different forms of immunotherapy. Our preliminary data show that the GBM TME specifically reprogrammed a subset of immunosuppressive neutrophils into cells with prolonged lifespans, providing abnormally high levels of long-lasting immunosuppressive cells in tumor beds. Immunosuppressive neutrophils showed boosted glucose metabolism, which correlated with high resistance to ferroptosis and high levels of histone lactylation (Kla). Since neutrophils are generally considered short-life cells, it becomes important to understand if and how local tumoral cues are linked to adaptive changes enabling survival of specific neutrophil subsets. Based on our preliminary key observations, we hypothesize that actionable histone lactylation-driven resistance to ferroptosis selectively maintains the pool of immunosuppressive neutrophils in hypoxic niches of tumors. We will test this hypothesis through the following aims: Aim1. To define metabolic cues that sustain immunosuppressive neutrophils in tumor beds; Aim2. To dissect the glucose catabolism-driven epigenetic mechanism determining resistance to cell death of immunosuppressive neutrophils; Aim3. To establish the therapeutic potential of targeting suppressive neutrophils. Thus, the proposed studies will elucidate tumor- induced metabolic and epigenetic determinants that sustain the pool of immunosuppressive neutrophils in tumor beds. Our work will exert a profound effect in the field by providing a mechanistic rationale to specifically target a major immunosuppressive, tumor-promoting component of the GBM TME, therefore contributing to the refinement and expansion of therapeutic approaches to overcome immunosuppression and enhance the efficacy of immunotherapy. Project Number: 1R01CA303116-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Filippo Veglia | Institution: WISTAR INSTITUTE, PHILADELPHIA, PA | Award Amount: $651,940 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368232