Liquid Biopsy Biomarkers for Predicting and Monitoring Immunotherapy Response in Lung Cancer

Background: While Immune Checkpoint Inhibitors (ICIs) have significantly improved outcomes in lung cancer (LC), clinical responses remain heterogeneous. Static tissue biomarkers, like PD-L1, and tumor mutational burden (TMB) are limited by intratumoral heterogeneity and the inability to track temporal changes. This review aims to evaluate the current state and future potential of liquid biopsy as a dynamic tool for patient selection, treatment monitoring, and the identification of resistance mechanisms in LC immunotherapy. Methods: A literature search was conducted in the PubMed database up to March 2026. We identified 65 eligible publications, including clinical trials, observational studies, and systematic reviews, focusing on liquid biopsy analytes such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and soluble immune mediators. Results: Liquid biopsy provides a “pooled” representation of the total tumor burden, overcoming the spatial limitations of tissue biopsy. Key findings include that dynamic changes in ctDNA and bTMB can predict molecular progression weeks before radiological assessment; blood-based PD-L1 monitoring (soluble, exosomal, or on CTCs) correlates with survival outcomes and offers a real-time readout of immune checkpoint activity; novel markers like tumor-macrophage fusion (TMF) cells and cytokine signatures provide unique insights into the systemic immune microenvironment. Conclusions: Liquid biopsy is evolving from a complementary diagnostic tool into a central pillar of precision immuno-oncology. Although technical standardization remains a challenge, the integration of multi-omic blood-based biomarkers represents the future of personalized lung cancer management.