Phosphatidylserine Externalization in Cancer: Biology, Immune Suppression, and Emerging Theragnostic Strategies

TL;DR

This paper reviews how phosphatidylserine (PS) exposure in cancer cells helps tumors evade the immune system and explores new treatments targeting PS for cancer therapy.

Contribution

The paper provides a comprehensive review of PS biology in cancer and highlights emerging PS-targeted theragnostic strategies.

Findings

Chronic PS externalization in cancer cells contributes to immune suppression and tumor progression.

PS-targeted therapies like bavituximab and SapC-DOPS/BXQ-350 show promise in combination with existing cancer treatments.

PS serves as a unifying biomarker for tumor stress and therapeutic vulnerability.

Abstract

Phosphatidylserine (PS) externalization is a conserved membrane stress signal that becomes chronically dysregulated in cancer cells and tumor-associated endothelium. In vivo, PS does not exist as a free lipid signal but is presented in specific membrane-associated forms, including apoptotic or stressed cell surfaces, PS-rich extracellular vesicles, and circulating lipid particles. Unlike apoptosis-associated transient PS exposure, malignant PS externalization arises from metabolic rewiring, oxidative stress, epigenetic silencing of flippases, and microenvironmental cues, creating an immunosuppressive interface across the tumor–host boundary. This review synthesizes mechanistic, immunological, and clinical evidence on PS biology, including its roles in tumor immune evasion, extracellular vesicle-mediated systemic suppression, and vascular remodeling. We further summarize the development and evaluation of PS-targeted therapeutic platforms—such as bavituximab, SapC-DOPS/BXQ-350, and PS-directed imaging agents—and highlight their translational potential in combination with radiotherapy, chemotherapy, and checkpoint inhibitors. Chronic PS externalization, as manifested through distinct cellular and vesicular carriers, represents a unifying biomarker of tumor stress, immune suppression, and therapeutic vulnerability, offering a next-generation axis for theragnostic cancer management.

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