Tumor mutational burden for the prediction of PD-(L)1 blockade efficacy in cancer: challenges and opportunities

Tumor mutational burden (TMB) is a biomarker that measures the number of somatic mutations in a tumor’s genome. TMB has emerged as a predictor of response to immune checkpoint inhibitors (ICIs) in various cancer types, and several studies have shown that patients with high TMB have better outcomes when treated with programmed death-ligand 1-based therapies. Recently, the Food and Drug Administration has approved TMB as a companion diagnostic for the use of pembrolizumab in solid tumors. However, despite its potential, the use of TMB as a biomarker for immunotherapy efficacy is limited by several factors. Here we review the limitations of TMB in predicting immunotherapy outcomes in patients with cancer and discuss potential strategies to optimize its use in the clinic. •TMB has been proposed as a biomarker of ICI efficacy across cancers, but its use in the clinic remains elusive.•Technical and biological factors limit the accuracy of TMB for the prediction of ICI efficacy in patients with cancer.•Cancer-specific thresholds should be considered to identify patients who are most likely to benefit from ICI.•TMB standardization and integration with other biomarkers can improve its predictive accuracy in patients with cancer.