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Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity

Tianyi Liu, Meng Zhang, Tatyanah Farsh, Haolong Li, Audrey Kishishita, Abhilash Barpanda, Stanley G. Leung, Jun Zhu, Hyuncheol Jung, Junjie Tony Hua, Xiaolin Zhu, Alexander B. Kim, Young Ah Goo, Minsoo Son, Jaenyeon Kim, Aish Subramanian, Martin Sjöström, Katherine C. Fuh, Jocelyn S. Chapman, Julia Carnevale, Luke A. Gilbert, Aparna Lakkaraju, Peter M. Bruno, David Quigley, Arun P. Wiita, Felix Y. Feng and Carl J. DeSelm ()
Additional contact information
Tianyi Liu: Helen Diller Family Comprehensive Cancer Center
Meng Zhang: Helen Diller Family Comprehensive Cancer Center
Tatyanah Farsh: Helen Diller Family Comprehensive Cancer Center
Haolong Li: Helen Diller Family Comprehensive Cancer Center
Audrey Kishishita: San Francisco
Abhilash Barpanda: San Francisco
Stanley G. Leung: Helen Diller Family Comprehensive Cancer Center
Jun Zhu: Helen Diller Family Comprehensive Cancer Center
Hyuncheol Jung: Gladstone–UCSF Institute of Genomic Immunology
Junjie Tony Hua: Helen Diller Family Comprehensive Cancer Center
Xiaolin Zhu: Helen Diller Family Comprehensive Cancer Center
Alexander B. Kim: Washington University School of Medicine
Young Ah Goo: Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine
Minsoo Son: Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine
Jaenyeon Kim: Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine
Aish Subramanian: Helen Diller Family Comprehensive Cancer Center
Martin Sjöström: San Francisco
Katherine C. Fuh: Helen Diller Family Comprehensive Cancer Center
Jocelyn S. Chapman: Helen Diller Family Comprehensive Cancer Center
Julia Carnevale: Helen Diller Family Comprehensive Cancer Center
Luke A. Gilbert: Helen Diller Family Comprehensive Cancer Center
Aparna Lakkaraju: University of California San Francisco
Peter M. Bruno: Helen Diller Family Comprehensive Cancer Center
David Quigley: Helen Diller Family Comprehensive Cancer Center
Arun P. Wiita: San Francisco
Felix Y. Feng: Helen Diller Family Comprehensive Cancer Center
Carl J. DeSelm: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Macrophages infiltrate solid tumors and either support survival or induce cancer cell death through phagocytosis or cytotoxicity. To uncover regulators of macrophage cytotoxicity towards cancer cells, we perform two co-culture CRISPR screens using CAR-macrophages targeting different tumor associated antigens. Both identify ATG9A as an important regulator of this cytotoxic activity. In vitro and in vivo, ATG9A depletion in cancer cells sensitizes them to macrophage-mediated killing. Proteomic and lipidomic analyses reveal that ATG9A deficiency impairs the cancer cell response to macrophage-induced plasma membrane damage through defective lysosomal exocytosis, reduced ceramide production, and disrupted caveolar endocytosis. Depleting non-cytotoxic macrophages using CSF1R inhibition while preventing ATG9A-mediated tumor membrane repair enhances the anti-tumor activity of therapeutic antibodies in mice. Thus, macrophage cytotoxicity plays an important role in tumor elimination during antibody or CAR-macrophage treatment, and inhibiting tumor membrane repair via ATG9A, particularly in combination with cytotoxic macrophage enrichment through CSF1R inhibition, improves tumor-targeting macrophage efficacy.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60745-x

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DOI: 10.1038/s41467-025-60745-x

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