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

Award Number: R01CA303116
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/19/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Elucidation of targetable mechanisms sustaining immunosuppressive neutrophils in the brain tumor microenvironment - PROJECT SUMMARY 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $651,940 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	1	5/20/2026	NEW	$651,940
														Subtotal = $651,940

Grand Total All Awards = $651,940

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

Award Number: R01CA303116

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/19/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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