2. Academic Validation
  3. Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity

Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity

  • Nat Immunol. 2026 Apr;27(4):750-761. doi: 10.1038/s41590-026-02452-3.
Zhenrui Li 1,  Beisi Xu 2,  Piyush Sharma 3,  Cliff Guy 3,  Emilio Boada-Romero 3,  Katherine Verbist 3,  Ao Guo 3 4,  Luigi Mari 3,  Suresh Poudel 3,  Mao Yang 3,  Douglas R Green 5
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
  • 2 Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Key Laboratory of Immnunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
PMID: 41776100 DOI: 10.1038/s41590-026-02452-3
Abstract

The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves Anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an Integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active Integrin barrier requires the Rubicon-VPS34 complex, which recruits Phospholipase D (PLD) to regulate Integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves Anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.

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