Tumor Mutational Burden (TMB) is a promising biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab. The Food and Drug Administration (FDA) has approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have high TMB (TMB-H), who have progressed following prior treatment and who have no satisfactory alternative treatment options. This marks a significant step in the personalized medicine approach to cancer treatment. Despite this advancement, the use of TMB as a biomarker is subject to several limitations: 1. **Standardization and Thresholds:** There needs to be more standardization in the measurement of TMB. Different sequencing panels and bioinformatics pipelines can yield different TMB scores for the same tumor sample. Additionally, the threshold for what constitutes “high” TMB can vary between studies and clinical trials, affecting the selection of patients for immunotherapy. 2. **Tumor Heterogeneity:** Tumors can be heterogeneous, meaning that different tumor areas may have different mutational profiles. A single biopsy may not accurately reflect the overall TMB of the tumor, which can influence the assessment of the patient’s candidacy for ICI therapy. 3. **Dynamic Nature of TMB:** TMB can change over time and in response to therapy. This dynamic nature means that a TMB measurement at one point in time may not be representative of the tumor’s mutational burden at a later date. 4. **Complexity of Immune Response:** The immune response to cancer is complex and influenced by many factors beyond TMB, such as neoantigens, the tumor microenvironment, the patient’s immune status, and other genomic alterations. Therefore, while TMB can indicate the likelihood of response to ICIs, it is not the only factor at play. 5. **Cost and Accessibility:** Comprehensive genomic profiling to determine TMB can be expensive and is not universally available. This may limit its use to specific settings or patient populations. 6. **Clinical Evidence:** While evidence supports the use of TMB as a biomarker, research is needed on its predictive value, and more research is needed to optimize and fully understand its use in clinical practice. Some studies have shown mixed results regarding the correlation between TMB and response to ICIs, indicating that more robust and large-scale studies are needed. 7. **Regulatory Challenges:** The regulatory landscape for biomarker-driven therapies is complex, and as new data emerge, recommendations and approvals may evolve, affecting the use of TMB as a companion diagnostic. To overcome these limitations, ongoing research efforts focus on better understanding the role of TMB in the context of other biomarkers, improving the standardization of TMB measurement, and developing more comprehensive approaches to predict patient response to ICIs. As our understanding of cancer biology and the immune system improves, the predictive value of TMB and its integration into clinical decision-making will likely become more refined.   https://www.annalsofoncology.org/article/S0923-7534(24)00084-X/fulltext?rss=yes