Al-Karawi AS, Al-Budairi AS. Soluble immunosuppressive checkpointome of mesenchymal stromal cells: Immunoregulatory mechanisms and a conceptual framework for potency assessment. World J Stem Cells 2026; 18(10): 125673 [DOI: 10.4252/wjsc.125673]
Corresponding Author of This Article
Abdullah Salim Al-Karawi, Researcher, Department of Microbiology, College of Science, Mustansiriyah University, Baghdad 0011, Iraq. abdullah.s.shaker@uomustansiriyah.edu.iq
Research Domain of This Article
Immunology
Article-Type of This Article
review-article
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World J Stem Cells. Oct 26, 2026; 18(10): 125673 Published online Oct 26, 2026. doi: 10.4252/wjsc.125673
Soluble immunosuppressive checkpointome of mesenchymal stromal cells: Immunoregulatory mechanisms and a conceptual framework for potency assessment
Abdullah Salim Al-Karawi, Ali Saad Al-Budairi
Abdullah Salim Al-Karawi, Department of Microbiology, College of Science, Mustansiriyah University, Baghdad 0011, Iraq
Ali Saad Al-Budairi, Branch of Biology, Department of Science, College of Basic Education, Wasit University, Kut 0011, Iraq
Author contributions: Al-Karawi AS conceived and designed the review, performed the literature search and evidence synthesis, prepared the figures and tables, and wrote the manuscript; Al-Budairi AS contributed to the literature search, the interpretation of the evidence and the critical revision of the manuscript for important intellectual content. All authors read and approved the final version.
AI contribution statement: The authors declare that no AI tools were used in the development or writing of this manuscript and take full responsibility for its integrity, accuracy, and originality.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Abdullah Salim Al-Karawi, Researcher, Department of Microbiology, College of Science, Mustansiriyah University, Baghdad 0011, Iraq. abdullah.s.shaker@uomustansiriyah.edu.iq
Received: July 15, 2026 Revised: September 7, 2026 Accepted: October 20, 2026 Published online: October 26, 2026 Processing time: 105 Days and 12 Hours
Abstract
Mesenchymal stromal cells (MSCs) are among the most widely investigated platforms in regenerative and immune-directed therapy, yet the molecular basis of their immunosuppressive activity remains incompletely defined. Classical accounts emphasise indoleamine 2,3-dioxygenase, prostaglandin E2, nitric oxide and extracellular vesicles (EVs), while a parallel secretory output has attracted comparatively little attention: The release of soluble immune checkpoint molecules. Soluble programmed death ligand 1 and 2, galectin-9, galectin-1 and the secreted human leukocyte antigen-G5 isoform are each documented in MSC conditioned medium, and each has been linked functionally to suppression of T-cell proliferation, induction of effector-cell apoptosis, or expansion of regulatory T cells. These proteins are generated through proteolytic ectodomain shedding, alternative splicing, or association with small EVs, and their abundance is strongly conditioned by inflammatory licensing. This review consolidates fragmented, single-molecule evidence into a proposed conceptual immunoregulatory framework, the MSC soluble immunosuppressive checkpointome. The framework is explicitly a conceptual grouping and not a physically interacting or experimentally validated synergistic protein complex; coordinated or synergistic action among its members has not been demonstrated. For clarity, the framework is defined operationally to encompass three physically distinct extracellular species, namely shed ectodomains, secreted splice isoforms and extracellular-vesicle-associated checkpoint proteins, and this distinction is applied consistently in the text, tables and figures. It groups molecules with experimentally demonstrated MSC release and immunoregulatory activity while distinguishing them from biologically plausible candidates whose secretion by MSCs has not yet been directly demonstrated. We then consider a translational application that has not been systematically explored, namely the use of secreted checkpoints as pharmacodynamic and potency markers, addressing a long-standing obstacle to standardising MSC product potency for regulatory release. We further discuss how a composite, multi-marker checkpoint signature, integrated with predictive and decision-support modelling, could inform donor selection, batch qualification and patient stratification. Because current evidence is largely associative and derives from heterogeneous platforms, we set out the methodological requirements that must be met before clinical translation.
Core Tip: Mesenchymal stromal cells release a defined set of soluble immune checkpoint proteins, notably soluble programmed death ligand 1 and 2, galectin-9, galectin-1 and the secreted human leukocyte antigen-G5 isoform. Treated separately until now, they are here proposed as a conceptual inducible module termed the soluble checkpointome. Because its abundance rises with inflammatory licensing and tracks with suppressive capacity, it offers a licensed, cell-free, multi-analyte panel well suited to the potency assays regulators require, and amenable to composite scoring supported by machine learning.
