Soluble Immune Checkpoint Biomarkers in Oncology

Soluble immune checkpoint biomarkers comprise circulating forms of inhibitory molecules that ordinarily regulate T-cell activation via receptor–ligand interactions at the cell surface. Generated by alternative splicing, proteolytic cleavage or secretion from immune and tumour cells, these soluble mediators—including soluble PD-1, soluble PD-L1 and soluble CTLA-4—persist in plasma and represent a non-invasive window into the status of antitumour immunity. Their concentrations have been correlated with disease stage, prognosis and resistance to immune checkpoint inhibitors across a spectrum of solid tumours such as non-small cell lung cancer, melanoma and hepatocellular carcinoma. Beyond their diagnostic and prognostic value, soluble checkpoint molecules may actively modulate immune responses by acting as decoys or by attenuating effector T-cell functions, thereby influencing therapeutic outcomes. Technological advances in multiplex immunoassays and chemiluminescence detection have improved sensitivity for these low-abundance proteins, enabling longitudinal monitoring during chemotherapy, targeted therapy, radiotherapy and immunotherapy. The global pursuit of soluble immune checkpoints extends from basic investigation of their biogenesis and function to clinical translation as biomarkers for patient stratification, treatment monitoring and the design of combinatorial strategies that overcome immunotherapy resistance.

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Soluble Immune Checkpoint Biomarkers in Oncology publication trend

The graph below shows the total number of articles in soluble immune checkpoint biomarkers in oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint: An inhibitory pathway of receptors and ligands that dampens T-cell activation to maintain self-tolerance and prevent autoimmunity.

Soluble immune checkpoint: A non-membrane-bound form of an immune checkpoint molecule released into the circulation by splicing or proteolysis.

PD-1 (Programmed cell death protein 1): An inhibitory receptor on T cells that, upon binding PD-L1, limits T-cell proliferation and cytokine production.

PD-L1 (Programmed death-ligand 1): A ligand for PD-1 expressed on tumour cells and immune cells that transmits an inhibitory signal to T cells.

CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4): A co-inhibitory receptor on T cells that competes with CD28 for CD80/CD86 binding, modulating early immune activation.

Tumour microenvironment: The cellular milieu surrounding a tumour, including immune cells, stromal cells and extracellular matrix, which shapes tumour growth and therapy response.

Immunotherapy resistance: The failure of immune-based treatments to achieve sustained tumour regression, often due to adaptive changes in tumour or immune cell populations.

References

1. Soluble receptors in cancer: mechanisms, clinical significance, and therapeutic strategies. Experimental & Molecular Medicine (2024).
2. Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies. Journal of Experimental & Clinical Cancer Research (2024).
3. Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade. Journal of Clinical Investigation (2024).