Targeting the PSGL-1 Glycoprotein in Cancer: Cellular Mechanisms and Emerging Immunotherapeutic Strategies

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.