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Publications

Journal Article Review Epublish 2 citations

PubMed: 40069722 DOI: 10.1186/s12964-025-02090-6

Dys-regulated phosphatidylserine externalization as a cell intrinsic immune escape mechanism in cancer.

Cell Commun Signal 23(1):131

Authors: Rachael Pulica, Ahmed Aquib, Christopher Varsanyi, Varsha Gadiyar, Ziren Wang, Trevor Frederick, David C Calianese, Bhumik Patel, Kenneth Vergel de Dios, Victor Poalasin, Mariana S De Lorenzo, Sergei V Kotenko, Yi Wu, Aizen Yang, Alok Choudhary, Ganapathy Sriram, Raymond B Birge

Affiliations

  • Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
  • Department of Cell Biology and Molecular Medicine, 185 South Orange Ave, Newark, NJ, 07103, USA.
  • Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Cyrus Tang Medical Institute, Soochow University, Suzhou, China.
  • International Center for Public Health, Public Health Research Institute, Newark, NJ, 07103, USA.
  • Department Biological, Chemical and Environmental Sciences, Wheaton College, 26 E Main St, Norton, MA, 02766, USA.
  • Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.

Abstract

The negatively charged aminophospholipid, phosphatidylserine (PS), is typically restricted to the inner leaflet of the plasma membrane under normal, healthy physiological conditions. PS is irreversibly externalized during apoptosis, where it serves as a signal for elimination by efferocytosis. PS is also reversibly and transiently externalized during cell activation such as platelet and immune cell activation. These events associated with physiological PS externalization are tightly controlled by the regulated activation of flippases and scramblases. Indeed, improper regulation of PS externalization results in thrombotic diseases such as Scott Syndrome, a defect in coagulation and thrombin production, and in the case of efferocytosis, can result in autoimmunity such as systemic lupus erythematosus (SLE) when PS-mediated apoptosis and efferocytosis fails. The physiological regulation of PS is also perturbed in cancer and during viral infection, whereby PS becomes persistently exposed on the surface of such stressed and diseased cells, which can lead to chronic thrombosis and chronic immune evasion. In this review, we summarize evidence for the dysregulation of PS with a main focus on cancer biology and the pathogenic mechanisms for immune evasion and signaling by PS, as well as the discussion of new therapeutic strategies aimed to target externalized PS. We posit that chronic PS externalization is a universal and agnostic marker for diseased tissues, and in cancer, likely reflects a cell intrinsic form of immune escape. The continued development of new therapeutic strategies for targeting PS also provides rationale for their co-utility as adjuvants and with immune checkpoint therapeutics.

MeSH

Cells, Neoplasms, Cell Communication, Therapeutics, Apoptosis, Phosphatidylserines, Immune Evasion

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