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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker
Open accessAbstract
Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.
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“In certain tumour types, the number of neoantigens in a tumour (or tumour mutational burden (TMB)) is correlated with responsiveness to ICIs67,68.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [67]
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“In this context, many studies have analyzed the relationship between tumor mutational burden (TMB) and immune checkpoint inhibitor (ICI) efficacy in different tumors [12].”
BackgroundResultCottrell, T. R., Lotze, M. T., Ali, A. M., Bifulco, C. B., Capitini, C. M., Chow, L. Q. M., Cillo, A. R., Collyar, D. E., Cope, L., Deutsch, J. S., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010928 · Cited by 65
Wang, H., Liu, J., Jiang, Y., Wang, Z., Zhang, Z., Peng, J., Wang, Y., & Li, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.943389 · Cited by 54
“Furthermore, our research founded a positive correlation between TMB and immune score and a negative correlation between TMB and tumor purity, suggesting that patients with higher TMB presented more active immune activity, which may be because higher TMB results in more neo-ant igens , increas ing chances for T-ce l l…”
Xu, S., Zheng, Y., Ye, M., Shen, T., Zhang, D., Li, Z., & Lu, Z. (2024) · BMC Cancer · doi:10.1186/s12885-024-12843-0 · Cited by 53
Anagnostou, V., Landon, B. V., Medina, J. E., Forde, P. M., & Velculescu, V. E. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abo3958 · Cited by 52
“Moreover, several technical and biological limitations preclude the broad use of TMB as a universal biomarker of response for ICI (35).”
BackgroundCAR T cell therapies for diffuse midline glioma
Thomas, B. C., Staudt, D. E., Douglas, A. M., Monje, M., Vitanza, N. A., & Dun, M. D. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.07.007 · Cited by 53
Tumor Mutational Burden in Breast Cancer: Current Evidence, Challenges, and Opportunities
Barroso‐Sousa, R., Pacifico, J. P. M., Sammons, S. L., & Tolaney, S. M. (2023) · Cancers · doi:10.3390/cancers15153997 · Cited by 54
“Before we can fully develop TMB as a predictive biomarker of immunotherapy benefit in breast cancer, we must address some remaining challenges (Table 2) [55,56].”
BackgroundNext-generation sequencing methodologies to detect low-frequency mutations: “Catch me if you can”
Menon, V., & Brash, D. E. (2023) · Mutation Research - Reviews in Mutation Research · doi:10.1016/j.mrrev.2023.108471 · Cited by 48
Progresses in biomarkers for cancer immunotherapy
Lin, X., Zong, C., Zhang, Z., Fang, W., & Xu, P. (2023) · MedComm · doi:10.1002/mco2.387 · Cited by 50
Chang, L.-C., Liu, J., Zhu, J.-L., Guo, S., Wang, Y., Zhou, Z., & Wei, X. (2025) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2024.0376 · Cited by 72
“A high TMB is positively associated with more tumor-associated neoantigens and greater immunotherapy effectiveness 80,81 .”
Wehrle, C. J., Hong, H., Kamath, S. D., Schlegel, A. A., Fujiki, M., Hashimoto, K., Kwon, C. H. D., Miller, C. C., Walsh, R. M., & Aucejo, F. (2024) · Annals of Surgery · doi:10.1097/sla.0000000000006386 · Cited by 52
“10 Preliminary results from the Imbrave050 trial support a potential role for adjuvant immunotherapy in HCC, though this is not yet the current standard of care.”
Sinha, N., Sinha, S., Valero, C., Schäffer, A. A., Aldape, K., Litchfield, K., Chan, T. A., Morris, L. G. T., & Ruppin, E. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-2542 · Cited by 51
Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy
Li, T., Wang, X., Niu, M., Wang, M., Zhou, J., Wu, K., & Yi, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1196970 · Cited by 52
“The phosphorylated domains recruit tyrosine phosphatases, SHP-2 and SHP-1, which are capable of impeding critical factors in TCR signaling (36–38).”
BackgroundInfluentialMurray, J. C., Sivapalan, L., Hummelink, K., Balan, A., White, J. R., Niknafs, N., Rhymee, L., Pereira, G., Rao, N., Weksler, B., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1469 · Cited by 47
“…and immune biomarkers—from tumor mutational burden to immune-related gene-expression signatures—have been evaluated as predictors of immunotherapy response (2, 3); however, with the exception of microsatellite instability, most of these putative biomarkers fail to consistently predict outcomes.”
Review of Personalized Medicine and Pharmacogenomics of Anti-Cancer Compounds and Natural Products
Zhou, Y., Peng, S., Wang, H., Cai, X., & Wang, Q. (2024) · Genes · doi:10.3390/genes15040468 · Cited by 49
“Moreover, only 3–13% of patients can choose personalized therapy through individual genomic analysis [146].”
BackgroundAssessing personalized responses to anti-PD-1 treatment using patient-derived lung tumor-on-chip
Veith, I., Nurmik, M., Mencattini, A., Damei, I., Lansche, C., Brosseau, S., Gropplero, G., Corgnac, S., Filippi, J., Poté, N., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101549 · Cited by 49
“13,14 Besides cancer cells, stromal cell populations, such as cancer-associated fibro-blasts 15 and endothelial cells, 16 also contribute to immuno-therapy response or resistance.”
Lu, S., Wang, C., Ma, J., & Wang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1456030 · Cited by 49
Biomarkers for immunotherapy resistance in non-small cell lung cancer
Rother, C., John, T., & Wong, A. N. M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1489977 · Cited by 46
Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives
Aleksakhina, S. N., & Imyanitov, E. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222010931 · Cited by 41
“The correlation between high TMB and increased benefit from therapy has been observed for immune checkpoint inhibitors (ICIs) [82,83].”
BackgroundPark, J. C., Krishnakumar, H. N., & Saladi, S. V. (2022) · Current Oncology · doi:10.3390/curroncol29060334 · Cited by 42
“Generally, an increased TMB results in the production and expression of more neo-antigens on MHC proteins that can be recognized by T cells [56].”
BackgroundYin, X., Song, X., Deng, W., BLAKE, N. W., Luo, X., & Meng, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1483454 · Cited by 44
“Moreover, TMB-H is not a perfect predictive biomarker, as some TMB-L patients also respond well to immunotherapy (45, 46).”
Ding, Q., Liu, H., Yan, L., Chen, L., Chen, Y., Kim, J. S., & Mei, L. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202505911 · Cited by 42
Genomic and molecular landscape of homologous recombination deficiency across multiple cancer types
Shi, Z., Chen, B., Han, X., Gu, W., Liang, S., & Wu, L. (2023) · Scientific Reports · doi:10.1038/s41598-023-35092-w · Cited by 46
Seclì, L., Leoni, G., Ruzza, V., Siani, L., Cotugno, G., Scarselli, E., & D’Alise, A. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316591 · Cited by 43
“…found that a higher TMB is associated with improved clinical outcomes, likely due to the increased potential for generating a higher number of neoantigens that can trigger a robust immune response against cancer cells; however, this association may not be consistent across all cancer types [13,14].”
BackgroundMature tertiary lymphoid structures: important contributors to anti-tumor immune efficacy
Bao, X., Lin, X., Xie, M., Yao, J., Song, J., Ma, X., Zhang, X., Zhang, Y., Liu, Y., Han, W., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1413067 · Cited by 45
Jensen, C., Nissen, N. I., von Arenstorff, C. S., Karsdal, M. A., & Willumsen, N. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02133-z · Cited by 41
“It is challenging to detect the exact neoantigens that induce T cell responses, and TMB assessment in a tissue biopsy is limited by patient surgical risk, intratumor heterogeneity, different cut-off values, detection methods, and overlap between responding and non-responding patients [20, 31, 32, 48, 49].”
BackgroundEvolution and Progress of mRNA Vaccines in the Treatment of Melanoma: Future Prospects
Bafaloukos, D. I., Gazouli, I., Koutserimpas, C., & Samonis, G. (2023) · Vaccines · doi:10.3390/vaccines11030636 · Cited by 44
“Tumors carrying limited neoantigens may surpass immune surveillance, and be less responsive to immune checkpoint inhibitors [26,27].”
BackgroundImmunotherapy for Gestational Trophoblastic Neoplasia: A New Paradigm
Baas, I. O., Westermann, A. M., You, B., Bolze, P., Seckl, M. J., & Ghorani, E. (2023) · Gynecologic and Obstetric Investigation · doi:10.1159/000533972 · Cited by 39
Bao, Y., Qiao, Y., Choi, J. E., Zhang, Y., Mannan, R., Cheng, C., He, T., Zheng, Y., Yu, J., Gondal, M. N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2314416120 · Cited by 39
“C ), suggesting that the cancer cells did not completely lose B2M or IFN - γ pathway genes.”
BackgroundInfluentialHepatocellular Carcinoma Immunotherapy: Predictors of Response, Issues, and Challenges
Rizzo, A., Brunetti, O., & Brandi, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011091 · Cited by 41
“According to multiple studies, patients who have more TMB (greater than 10 mutations per million bases) after receiving ICIs have better response rates and longer survival times [64].”
BackgroundJiang, Q., Sun, J., Chen, H., Ding, C., Tang, Z., Ruan, Y., Liu, F., & Sun, Y. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.650673 · Cited by 36
Patkar, S., Chen, A., Basnet, A., Bixby, A., Rajendran, R., Chernet, R., Faso, S., Kumar, P. A., Desai, D., El-Zammar, O., et al. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00765-w · Cited by 41
“The clinical utility of other biomarkerssuchastheTumorMutationalBurden(TMB)hasbeenexplored inseveraldifferentclinicaltrials 11 – 14 .”
Chen, J., Niu, C., Yang, N., Liu, C., Zou, S., & Zhu, S. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106674 · Cited by 35
Liu, Y., Altreuter, J., Bodapati, S., Cristea, S., Wong, C. J., Wu, C. J., & Michor, F. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100444 · Cited by 39
“26 30 However, TMB is not predictive across all cancer types, and experimental measures of TMB are often inconsistent, which can limit comparisons across trials and datasets.”
BackgroundWang, Q., Zheng, C., Hou, H., Bao, X., Tai, H., Huang, X., Li, Z., Li, Z., Wang, Q., Pan, Q., et al. (2023) · Journal of Cancer · doi:10.7150/jca.89338 · Cited by 35
“Tumor mutational burden (TMB), along with its associated synchronous response to neoantigens, emerges as a robust and reliable indicator for monitoring the efficacy of immune checkpoint inhibitors (ICIs) (59-61).”
BackgroundTumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas
Yu, G., Pang, Y. K., Merchant, M., Kesserwan, C. A., Gangalapudi, V., Abdelmaksoud, A. A., Ranjan, A., Kim, O., Wei, J. S., Chou, H.-C., et al. (2021) · Cancers · doi:10.3390/cancers13236092 · Cited by 34
“Tumor mutation burden (TMB), which is often proportional to the neoantigen burden, has emerged as a promising predictive biomarker of immune response in melanoma and lung cancer [4].”
BackgroundMethod
Metadata
- Authors
- Jardim, D. L., Goodman, A., de Melo Gagliato, D., & Kurzrock, R.
- Affiliations
- Hospital Sírio-Libanês (BR)
- University of California San Diego (US)
- Corresponding author
- Kurzrock, Razelle
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 39
- Issue
- 2
- Pages
- 154-173
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC7878292
- OpenAlex
- W3097803258
- Cited by
- 1,192
- References
- 151
- Citations by year
- 2026: 134 · 2025: 263 · 2024: 294 · 2023: 276 · 2022: 171 · 2021: 53
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Astellas Pharma US
- National Cancer Institute (P30 CA023100)
- Janssen Pharmaceuticals
- AstraZeneca
- Bristol-Myers Squibb
- Genentech
- Roche
- EMD Serono
- Pfizer
- Meso Scale Diagnostics
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- tumor mutational burden, immunotherapy biomarkers, immune checkpoint inhibitors, neoantigens, MHC class I antigen presentation, T cell receptor repertoire, cancer immunotherapy response prediction
- MeSH terms
- Immune Checkpoint Inhibitors, Humans, Immunotherapy, Major Histocompatibility Complex, Mutation, Neoplasms, T-Lymphocytes, Biomarkers, Tumor
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