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Elucidation of a post-transcriptional regulatory node in macrophage function

Award Number: DP2CA325959
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Elucidation of a post-transcriptional regulatory node in macrophage function - SUMMARY/ABSTRACT Despite decades of study, we still do not understand how new macrophage subtypes arise from circulating monocytes and tissue-resident macrophages. Current models, built largely from RNA-sequencing and genetic perturbation studies, emphasize transcriptional reprogramming. However, these approaches cannot capture post-transcriptional events or protein-level acquisitions from other cells, leaving a major gap in our understanding of macrophage state transitions. We hypothesize that a non-cell autonomous regulatory mechanism, which we term protein redeployment, is a key initiating step in macrophage state transitions. In this process, macrophages directly acquire functional cell surface proteins from other cells during the recognition phase of phagocytosis. These proteins are incorporated into the macrophage membrane and meaningfully alter macrophage function. Because protein redeployment is transcriptionally silent, it is invisible to sequencing-based technologies. and its scale is not observable using field-standard low-throughput antibody panels. To overcome this barrier, we have developed a chemical proteomics platform that profiles macrophage protein composition at scale and determines the cell of origin for each protein. Our preliminary data show that redeployed proteins are functional, durable, and capable of modulating macrophage function. We focus our initial studies on understanding how otherwise healthy monocytes and tissue resident macrophages acquire the tumor associated macrophage (TAM) phenotype in solid tumors, since this is a widely studied and tractable system. TAMs are among the most abundant immune cells in solid tumors and their abundance strongly correlates with poor clinical outcomes. Yet do not understand how they arise. In this work, we will: 1. Define how protein redeployment alters macrophage state. We will determine how redeployment affects cytokine production, polarization, and the emergence of hallmark TAM features. 2. Quantify the durability and functional threshold for redeployed proteins and measure their impact on the macrophage surface proteome. 3. Map the scope of redeployment across macrophage uptake mechanisms beyond phagocytosis, including trogocytosis and efferocytosis, in non-malignant settings, and in the context of other phagocytic cell types. By revealing a mechanism that has been technically inaccessible until now, our work will answer a longstanding question in immunology: What initiates macrophage state transitions in health and disease? Beyond macrophage biology, this project will establish a new framework for identifying and interrogating non-cell autonomous regulatory nodes in immunology. In the future, our insights may able enable novel therapeutic strategies targeting macrophage reprogramming.


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 = $765,531 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Trans-NIH Research Support	000	1	9/22/2026	NEW	$765,531
														Subtotal = $765,531

Grand Total All Awards = $765,531

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Elucidation of a post-transcriptional regulatory node in macrophage function

Award Number: DP2CA325959

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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