Tumor Mutational Burden in Cancer Immunotherapy Response

Tumour mutational burden (TMB) has emerged as a key biomarker for predicting the efficacy of immune checkpoint blockade in oncology. High TMB is thought to increase the likelihood of generating neoantigens—novel peptide sequences presented on human leukocyte antigen molecules—that provoke a robust T-cell response. Clinical studies have demonstrated that patients with tumours harbouring elevated TMB often achieve higher objective response rates and prolonged progression-free and overall survival when treated with inhibitors of PD-1, PD-L1 or CTLA-4. Nonetheless, TMB is an imperfect proxy of tumour immunogenicity: variability in neoantigen quality, the heterogeneity of the tumour microenvironment and differences in antigen presentation pathways can all modulate therapeutic outcome. Recent efforts have therefore focused on refining the measurement of mutation load, dissecting the contribution of persistent mutational clones, and integrating parameters such as HLA diversity to improve patient stratification and guide combination treatment strategies.

Research from Nature Portfolio

Recent studies have emphasised the role of mutation persistence and antigen presentation in shaping immunotherapy response. One investigation identified a subset of mutations located in genomic regions resistant to loss—termed persistent TMB—which remain stable under immune pressure and correlate with an inflamed tumour microenvironment and sustained benefit from checkpoint blockade across multiple cancer types. Another work introduced a human leukocyte antigen tumour-antigen presentation score (HAPS), a composite metric combining predicted neoantigen binding affinity to HLA-I and allele divergence. High HAPS was associated with improved survival in patients receiving immune checkpoint inhibitors, and a neural network incorporating neoantigen generation, presentation and recognition factors improved discrimination of likely responders.

Tumor Mutational Burden in Cancer Immunotherapy Response publication trend

The graph below shows the total number of articles in tumor mutational burden in cancer immunotherapy response across all publications each year (not limited to Nature Index journals).

Technical terms

Tumour mutational burden (TMB): the total number of somatic coding mutations per megabase of tumour DNA, used as a biomarker for immunotherapy response.

Neoantigen: a mutation-derived peptide presented by HLA molecules that can be recognised by T cells as foreign.

Immune checkpoint inhibitors: therapeutic antibodies that block regulatory pathways in T cells—such as PD-1, PD-L1 or CTLA-4—to enhance anti-tumour immunity.

Tumour microenvironment: the complex milieu surrounding cancer cells, composed of immune cells, stromal elements and signalling molecules that influence tumour growth and response to therapy.

Persistent TMB (pTMB): the fraction of tumour mutations in genomic regions unlikely to undergo loss, which persist under the selective pressure of immunotherapy and drive durable immune control.

HLA tumour-antigen presentation score (HAPS): an integrated metric combining neoantigen binding affinity to HLA-I and allele diversity to predict likelihood of response to immune checkpoint blockade.

References

1. Persistent mutation burden drives sustained anti-tumor immune responses. Nature Medicine (2023).
2. Assessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy. Nature Communications (2024).
3. Association of High Tumor Mutation Burden in Non–Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels. JAMA Oncology (2022).
4. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Annals of Oncology (2021).
5. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges. Journal for ImmunoTherapy of Cancer (2019).