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Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity

Liu, Tianyi ; Zhang, Meng ; Farsh, Tatyanah ; Li, Haolong ; Kishishita, Audrey ; Barpanda, Abhilash ; Leung, Stanley G. ; Zhu, Jun ; Jung, Hyuncheol and Hua, Junjie Tony , et al. (2025) In Nature Communications 16(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
5616
publisher
Nature Publishing Group
external identifiers
  • pmid:40595560
  • scopus:105009728053
ISSN
2041-1723
DOI
10.1038/s41467-025-60745-x
language
English
LU publication?
yes
id
c4b83da5-b4d1-456f-860a-0a813c2c3247
date added to LUP
2025-10-27 15:04:51
date last changed
2025-10-27 15:05:33
@article{c4b83da5-b4d1-456f-860a-0a813c2c3247,
  abstract     = {{<p>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.</p>}},
  author       = {{Liu, Tianyi and Zhang, Meng and Farsh, Tatyanah and Li, Haolong and Kishishita, Audrey and Barpanda, Abhilash and Leung, Stanley G. and Zhu, Jun and Jung, Hyuncheol and Hua, Junjie Tony and Zhu, Xiaolin and Kim, Alexander B. and Goo, Young Ah and Son, Minsoo and Kim, Jaenyeon and Subramanian, Aish and Sjöström, Martin and Fuh, Katherine C. and Chapman, Jocelyn S. and Carnevale, Julia and Gilbert, Luke A. and Lakkaraju, Aparna and Bruno, Peter M. and Quigley, David and Wiita, Arun P. and Feng, Felix Y. and DeSelm, Carl J.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-60745-x}},
  doi          = {{10.1038/s41467-025-60745-x}},
  volume       = {{16}},
  year         = {{2025}},
}