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Identifying and targeting cancer immune evasion signals against macrophage surveillance

Award Number: R01CA303847
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Identifying and targeting cancer immune evasion signals against macrophage surveillance - Project Summary/Abstract Exciting advances in cancer immunology have identified numerous mechanisms that facilitate cancer cells’ ability to evade immune surveillance, leading to the rapid development of effective cancer immunotherapies. Tumor- associated macrophages (TAMs) are a predominant cell population within the tumor microenvironment (TME), continuously replenished by circulating monocytes. Targeting macrophages to activate their tumoricidal properties has emerged as a promising therapeutic strategy, applicable to both hematopoietic malignancies and solid tumors. Recent research has underscored the pivotal role of macrophage-mediated recognition and phagocytosis of cancer cells, a process known as “Programmed Cell Removal” (PrCR), in tumor surveillance and elimination. The efficacy of PrCR hinges on the dynamic interplay between cancer cells and macrophages. During tumorigenesis, cancer cells frequently upregulate anti-phagocytic “don’t eat me” pathways to counteract “eat me” signals, enabling them to evade PrCR. The blockade of “don’t eat me” signals leads to direct phagocytosis and elimination of living cancer cells by macrophages, as demonstrated in various preclinical cancer models and clinical trials. Despite the clear therapeutic potential of activating TAMs, significant challenges remain. In contrast to the well-established field of T cell immunotherapy, where numerous immune checkpoints have been extensively characterized, thus far, few phagocytosis checkpoints regulating macrophage-mediated PrCR have been identified, limiting the development of new PrCR-based cancer immunotherapies. In preliminary studies, employing a high-through phagocytosis-based CRISPR screening to investigate immune receptors containing putative immunoreceptor tyrosine-based inhibitory motif (ITIM), we identified receptors on macrophages as critical negative regulators of PrCR. Suppressing the activity of these receptors enhanced macrophage-mediated PrCR and inhibited tumor development in preclinical models. The overall objective of this study is to identify and characterize novel phagocytosis checkpoints and to elucidate their underlying mechanisms in facilitating cancer cell evasion of PrCR. In Aim 1, we will assess to what extent the suppression of the identified ITIM-containing receptors promotes PrCR of cancer cells, utilizing a combination of in vitro and in vivo assays. In Aim 2, we will interrogate the role of phagocytosis checkpoints in mediating the interaction between cancer cells and TAMs and remodeling the TME landscape. Aim 3 will focus on unraveling the molecular pathways that mediate PrCR inhibition and developing therapeutic strategies to target the extracellular molecular machinery of ITIM-containing receptors for PrCR activation. The successful completion of this study will significantly advance our understanding of the basic mechanisms underlying cancer immunosurveillance and offer innovative therapeutic strategies for the treatment of a variety of cancers.


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 = $694,015 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	5/5/2026	NEW	$694,015
														Subtotal = $694,015

Grand Total All Awards = $694,015

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Identifying and targeting cancer immune evasion signals against macrophage surveillance

Award Number: R01CA303847

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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