PD-L1 Status on Circulating Tumor Cells: A Promising Predictor in Advanced Lung Cancer With Immunotherapy

Immunotherapy has transformed treatment for advanced non–small cell lung cancer (NSCLC), but a new contender may reshape how clinicians decide who truly benefits: PD-L1 expression on circulating tumor cells (CTCs). As tissue biopsies continue to fall short—limited by invasiveness, sampling error, and tumor heterogeneity—liquid biopsy–based PD-L1 assessment is emerging as a dynamic, noninvasive predictor of response to PD-1/PD-L1 inhibitors.

Recent studies have focused on liquid biopsy, especially CTCs, which can be a noninvasive way to track the dynamic tumor biology and lead to a better prediction of immunotherapy response. The measurement of PD-L1 expression on CTCs is rapidly becoming noticed as the most likely predictive biomarker for the success of PD-1/PD-L1 inhibitor treatment in cases of advanced lung cancer.¹

Why CTC PD-L1 Status Matters

CTCs are cells that break off from a primary or metastatic tumor and enter the bloodstream. These cells can be separated by performing a simple blood draw. One of the main advantages of CTCs over tissue biopsies is their ability to provide information on the tumor phenotype in real time, while also capturing the heterogeneity of tumor cells that is present in different sites.² Regular tissue PD-L1 testing might classify tumors based on a single lesion; thus, immunoregulatory marker expression levels might not always be detected. By contrast, CTC PD-L1 can potentially illustrate a much more accurate reflection of disease biology and treatment susceptibility.³

A recently published prospective study of 52 patients with advanced lung cancer, in which PD-L1 expression on CTCs was assessed through a specialized liquid biopsy platform. At baseline, 50% of patients had PD-L1–positive CTCs, and these patients had markedly higher objective response rates (84.2%) to combined chemotherapy and PD-1/PD-L1 inhibitor therapy compared with patients without PD-L1–positive CTCs (36.8%). Additionally, the median progression-free survival (PFS) was significantly longer in the CTC PD-L1-positive group (16 months vs 4 months), and PD-L1 positivity on CTCs was a factor independently predicting both response and survival outcomes.¹ These results indicate that CTC PD-L1 status may help clinicians to select patients who are more likely to respond to immunotherapy combinations.

Evidence Supporting Predictive Value

Separate research in advanced NSCLC has also substantiated the possible predictive role of PD-L1 expression on CTCs. A study on NSCLC patients who received PD-1/PD-L1 inhibitors revealed that the presence of PD-L1-positive CTCs was linked to better patient outcomes, reflecting the practicability of this liquid biopsy method in real-world clinical scenarios.⁴ Previously, it has been demonstrated that PD-L1 levels on CTCs do not necessarily correlate with those in the tumor tissue, pointing out the unique and additive value of liquid biopsy over conventional tissue assays.⁵

Preliminary prospective data also suggest that patients who at baseline have PD-L1 expression on CTCs benefit longer from PFS when treated with PD-1/PD-L1 inhibitors compared to those patients without PD-L1 detectable on CTCs. Although more extensive prospective trials are still required, these results give a strong argument for including CTC PD-L1 evaluation in clinical research and in therapy decision-making.

Challenges and Clinical Integration

Despite promising results, several challenges remain before CTC PD-L1 can be broadly adopted in practice. Protocols for CTC isolation and PD-L1 detection require standardization, and cutoff values for defining PD-L1 positivity on CTCs vary across studies. Moreover, most evidence to date derives from relatively small cohorts; larger multicenter trials are necessary to confirm the biomarker’s predictive accuracy and reproducibility. The heterogeneity in detection platforms, PD-L1 antibodies, and analytical methods further complicates direct comparison between studies.

Nevertheless, if validated, CTC PD-L1 status could enhance stratification beyond tissue biopsy alone, offering clinicians a dynamic tool for selecting patients most likely to benefit from PD-1/PD-L1 blockade. Its noninvasive nature also supports longitudinal monitoring to detect changes in tumor biology over time.

Conclusion

Assessing the PD-L1 protein levels on the surface of CTCs is a novel development in the field of liquid biopsies that could have a significant impact on the treatment of advanced lung cancer. Although it is still very important to determine PD-L1 levels on tissue sections, the expression of PD-L1 on CTCs may be a more reliable marker of patient response to PD-1/PD-L1 checkpoint inhibitors and thereby lead to better patient selection and outcomes. More extensive clinical trials are necessary to validate the role of PD-L1 on CTCs and its inclusion as a standard biomarker in oncology practice.

REFERENCES

1. Wei, X., Chen, L., Yang, Z. et al. PD-L1 status on circulating tumor cells: a promising predictor in advanced lung cancer with PD-1/PD-L1 immunotherapies. Eur J Med Res (2026). doi:10.1186/s40001-026-03945-5

2. Dall’Olio FG, Gelsomino F, Conci N, et al. PD-L1 Expression in Circulating Tumor Cells as a Promising Prognostic Biomarker in Advanced Non–small-cell Lung Cancer Treated with Immune Checkpoint Inhibitors. Clinical Lung Cancer. 2021;22(5):423-431. doi:10.1016/j.cllc.2021.03.005

3. Zhou Q, Liu X, Li J, et al. Circulating tumor cells PD-L1 expression detection and correlation of therapeutic efficacy of immune checkpoint inhibition in advanced non-small-cell lung cancer. Thorac Cancer. 2023;14(5):470-478. doi:10.1111/1759-7714.14767

4. Strati A, Economopoulou P, Lianidou E, Psyrri A. Clinical Significance of PD-L1 Status in Circulating Tumor Cells for Cancer Management during Immunotherapy. Biomedicines. 2023; 11(6):1768. doi:10.3390/biomedicines11061768

5. Cheng Y, Wang T, Xin Lv, et al. Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer. 2020;Volume 12:2069-2078. doi:10.2147/cmar.s245425