Targeting the PSGL-1 glycoprotein in cancer: cellular mechanisms and emerging immunotherapeutic strategies.
- 1i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Abstract
Immune checkpoint immunotherapy has transformed contemporary oncology, establishing a new paradigm across diverse malignancies. P-selectin glycoprotein ligand-1 (PSGL-1; CD162) emerged as a new immunotherapeutic target. Initially characterized as a glycosylated selectin ligand controlling leukocyte rolling, adhesion, and trafficking, PSGL-1 is now recognized as a multifunctional immunoregulatory receptor with therapeutic relevance in cancer. Its mucin-like structure, specific glycosylation, tyrosine sulfation, and cellular context enable functional interactions with several ligands, including selectins and V-domain immunoglobulin suppressor of T cell activation (VISTA). PSGL-1 is known to shape immune homeostasis, T-cell activation, effector and memory T-cell differentiation, myeloid-cell function, and tumor immune evasion. In chronic infection and cancer models, PSGL-1 restrains antigen-driven T-cell responses and contributes to dysfunctional or exhausted T-cell states, supporting its classification as a checkpoint-like regulator of immunity. Importantly, genetic deletion or antibody-mediated blockade of PSGL-1 enhances anti-tumor immunity in preclinical cancer models by increasing tumor-infiltrating T-cell activation and promoting immunostimulatory myeloid phenotypes. These changes in tumor-infiltrating immune cells are associated with reduction of tumor growth, synergism with PD-1/PD-L1 blockade, and improvement of chimeric antigen receptor (CAR) T-cell therapy. In blood cancers, where PSGL-1 is often expressed in malignant cells, PSGL-1 contributes to malignant cell homing, tissue dissemination, chemoresistance, and antibody-induced tumor-cell apoptosis. Overall, PSGL-1 represents a promising candidate for next-generation cancer immunotherapy, with potential to stimulate anti-tumor immunity, remodel the tumor microenvironment, and target malignant hematopoietic cell properties.
Related
- Targeting the NLRP3 inflammasome in rheumatoid arthritis fibroblast-like synoviocytes: pathogenic mechanisms, therapeutic strategies, and translational perspectives
- Bidirectional cellular senescence crosstalk in MASLD: mechanisms, disease progression, and treatment strategies
- Targeting Bacillus cereus biofilms: Biocontrol strategies, mechanisms of action, and emerging challenges
- Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer’s Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives
- Structural basis for cross-alphaherpesvirus neutralization by an antibody targeting a conserved hotspot on glycoprotein B
BibTeX
@article{pereira2026targeting,
title = {{Targeting the PSGL-1 glycoprotein in cancer: cellular mechanisms and emerging immunotherapeutic strategies.}},
author = {João L Pereira and Nuno R Dos Santos},
journal = {Immunotherapy advances},
year = {2026},
month = oct,
doi = {10.1093/immadv/ltag023},
url = {https://europepmc.org/article/MED/42909984},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Targeting the PSGL-1 glycoprotein in cancer: cellular mechanisms and emerging immunotherapeutic strategies.
AU - João L Pereira
AU - Nuno R Dos Santos
PY - 2026
DA - 2026/10/10
JO - Immunotherapy advances
DO - 10.1093/immadv/ltag023
UR - https://europepmc.org/article/MED/42909984
AB - Immune checkpoint immunotherapy has transformed contemporary oncology, establishing a new paradigm across diverse malignancies. P-selectin glycoprotein ligand-1 (PSGL-1; CD162) emerged as a new immunotherapeutic target. Initially characterized as a glycosylated selectin ligand controlling leukocyte rolling, adhesion, and trafficking, PSGL-1 is now recognized as a multifunctional immunoregulatory receptor with therapeutic relevance in cancer. Its mucin-like structure, specific glycosylation, tyrosine sulfation, and cellular context enable functional interactions with several ligands, including selectins and V-domain immunoglobulin suppressor of T cell activation (VISTA). PSGL-1 is known to shape immune homeostasis, T-cell activation, effector and memory T-cell differentiation, myeloid-cell function, and tumor immune evasion. In chronic infection and cancer models, PSGL-1 restrains antigen-driven T-cell responses and contributes to dysfunctional or exhausted T-cell states, supporting its classification as a checkpoint-like regulator of immunity. Importantly, genetic deletion or antibody-mediated blockade of PSGL-1 enhances anti-tumor immunity in preclinical cancer models by increasing tumor-infiltrating T-cell activation and promoting immunostimulatory myeloid phenotypes. These changes in tumor-infiltrating immune cells are associated with reduction of tumor growth, synergism with PD-1/PD-L1 blockade, and improvement of chimeric antigen receptor (CAR) T-cell therapy. In blood cancers, where PSGL-1 is often expressed in malignant cells, PSGL-1 contributes to malignant cell homing, tissue dissemination, chemoresistance, and antibody-induced tumor-cell apoptosis. Overall, PSGL-1 represents a promising candidate for next-generation cancer immunotherapy, with potential to stimulate anti-tumor immunity, remodel the tumor microenvironment, and target malignant hematopoietic cell properties.
SN - 2732-4303
ER -