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Metabolically Reprogramming Hepatic Macrophages to Conquer Immune Desert Tumors

Award Number: K99CA297030
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Metabolically Reprogramming Hepatic Macrophages to Conquer Immune Desert Tumors - PROJECT SUMMARY/ABSTRACT Tumors with different oncogenic mutations display diverse immunophenotypes that can affect CD8+ cytotoxic T lymphocyte (CTL)-mediated cancer immunosurveillance. Specifically, b-catenin activation leads to an “immune- desert” tumor microenvironment due to impairment of type 1 dendritic cell (DC1)-mediated CD8+ T cell priming, with mutations in the CTNNB1 gene among the most frequent oncogenic events in human hepatocellular carcinomas (HCCs). Of note, hepatic macrophages (hMfs) reside within a unique intra-vascular tissue niche with potential to act as antigen-presenting cells (APCs) to prime naïve T cells. Following our recent findings that monocyte-derived tumor-associated macrophages (TAMs) are capable of cross-presenting cancer cell antigens to CD8+ T cells and activation of the metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) potently affects macrophage differentiation and function, we will herein explore the effect of mTORC1 signaling on hMf APC functions in a murine model of b-catenin-driven HCC. Our preliminary data showed that hMfs lacking the mTORC1 suppressor TSC1 could correct the CD8+ T cell priming defects in the “immune-desert” HCC model and restore cancer immunity. Furthermore, TSC1-deficient hMfs display enhanced mitochondrial activities with the malate-aspartate shuttle playing a critical role to support macrophage reprogramming. Based on these observations, we hypothesize that hMfs can be reprogrammed via TSC1 deletion to overcome the “immune-desert” phenotype of b-catenin-driven HCC by acting as effective APCs to prime and activate CD8+ T cells, and this capability relies on their metabolic reprogramming. To test this hypothesis, I propose the following specific aims: 1) To determine whether and how TSC1-deficient TIM4- hMfs function as APCs to promote CD8+ T cell-mediated cancer immunity; 2) To define whether and how TSC1-deficient TIM4- hMfs are metabolically programmed to support CD8+ T cell-mediated cancer immunity. Completion of this project will generate mechanistic insights into the fundamental question of metabolic control of macrophage functions in cancer, and provide a novel therapeutic strategy to overcome immune evasion caused by defective DC-mediated T cell priming in “immune-desert” tumors. My long-term career goal is to become an independent investigator and lead a laboratory studying the metabolic function and mechanisms of tumor macrophages. To achieve this goal, I have devised a detailed career plan to gain skills in leadership, management, mentorship, grant writing, and scientific communication. I will work under the mentorship of Dr. Ming Li, a leader in the fields of cancer immunology and immunometabolism. Additionally, I have assembled an advisory committee comprised of Drs. Lionel Ivashkiv, Amaia Lujambio, Andrea Schietinger, and Hongbo Chi to provide me with complementary expertise and guidance in both scientific and career development. My research and career development plan, combined with the guidance of my mentor and advisors, as well as the outstanding academic environment at MSKCC, will serve as the bedrock for my independence in the field of tumor macrophage research.


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 = $145,336 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	2/27/2026	NON-COMPETING CONTINUATION	$145,336
														Subtotal = $145,336

Issue Date FY: 2025 ( Subtotal = $145,336 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	2/25/2025	NEW	$145,336
														Subtotal = $145,336

Grand Total All Awards = $290,672

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Metabolically Reprogramming Hepatic Macrophages to Conquer Immune Desert Tumors

Award Number: K99CA297030

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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