Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity

Nat Commun. 2025 Jul 1;16(1):5616. doi: 10.1038/s41467-025-60745-x.

Tianyi Liu ¹ ², Meng Zhang ¹ ², Tatyanah Farsh ¹ ², Haolong Li ¹ ², Audrey Kishishita ³, Abhilash Barpanda ⁴, Stanley G Leung ¹ ², Jun Zhu ¹ ², Hyuncheol Jung ⁵ ⁶, Junjie Tony Hua ¹ ², Xiaolin Zhu ¹ ⁶, Alexander B Kim ⁷ ⁸, Young Ah Goo ⁹, Minsoo Son ⁹, Jaenyeon Kim ⁹, Aish Subramanian ¹ ², Martin Sjöström ² ¹⁰ ¹¹, Katherine C Fuh ¹ ¹², Jocelyn S Chapman ¹ ¹², Julia Carnevale ¹ ⁵ ⁶ ¹³, Luke A Gilbert ¹ ¹⁴ ¹⁵, Aparna Lakkaraju ¹⁶ ¹⁷, Peter M Bruno ¹ ¹⁴, David Quigley ¹ ¹⁴ ¹⁸, Arun P Wiita ⁴ ¹⁹ ²⁰, Felix Y Feng ¹ ² ¹⁴, Carl J DeSelm ²¹ ²²

Affiliations

1 University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA.
2 Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, 94158, USA.
3 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
4 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 94158, USA.
5 Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, 94158, USA.
6 Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
7 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63108, USA.
8 Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St. Louis, MO, 63110, USA.
9 Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine, St. Louis, MO, 63108, USA.
10 Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden.
11 Division of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
12 Division of gynecologic oncology, University of California, San Francisco, CA, 94158, USA.
13 Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, 94129, USA.
14 Department of Urology, University of California, San Francisco, CA, 94158, USA.
15 Arc Institute, Palo Alto, CA, 94304, USA.
16 Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco, San Francisco, CA, 94143, USA.
17 Department of Ophthalmology, University of California San Francisco, San Francisco, CA, 94115, USA.
18 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.
19 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94143, USA.
20 Chan Zuckerberg Biohub San Francisco, San Francisco, CA, 94158, USA.
21 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63108, USA. deselmc@wustl.edu.
22 Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St. Louis, MO, 63110, USA. deselmc@wustl.edu.

PMID: 40595560 DOI: 10.1038/s41467-025-60745-x

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-114153

PLX5622

99.95%, CSF1R抑制剂

c-Fms

Neurological Disease

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