Predictive Biomarkers for Immune Checkpoint Inhibitor Efficacy: Challenges, Innovations, and a Pathway to Precision Medicine in the Era of Cancer Immunotherapy.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed oncology practice. However, treatment response remains heterogeneous, rendering predictive biomarkers critical for optimal patient care. The 3 established biomarkers, programmed death-ligand 1, tumor mutational burden (TMB), and microsatellite instability-high/deficient mismatch repair, are approved and clinically validated but are modest predictors of benefit. As a result, multiple novel predictive biomarkers remain under investigation. CONTENT: This review highlights established and investigational predictive ICI efficacy biomarkers. For established biomarkers, we describe biology, assay modalities, approved companion diagnostics, landmark studies, and notable limitations. Due to the multisystem nature of antitumor immune effects, investigational biomarkers span multiple domains, including tumor genomic biomarkers (e.g., mutational signatures, TMB, neoantigen clonality), tumor microenvironment (e.g., tumor-infiltrating lymphocytes [TILs], tertiary lymphoid structures), systemic immune biomarkers (e.g., cytokines, autoantibodies, glycoproteins, peripheral blood mononuclear cells), and the microbiome (e.g., gastrointestinal microbial diversity, responder-enriched taxa). SUMMARY: The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.