The role of neoantigens and tumor mutational burden in cancer immunotherapy: advances, mechanisms, and perspectives

Abstract

Cancer immunotherapy has revolutionized oncology by leveraging the immune system to combat tumors. Among various biomarkers, neoantigens and tumor mutational burden (TMB) have emerged as critical factors in tailoring personalized treatments. Neoantigens are tumor-specific peptides displayed on cancer cell surfaces, derived from somatic mutations. Recognized as "non-self" by the immune system, they trigger T-cell responses and enable therapies like personalized vaccines and adoptive T-cell transfer. Critically, neoantigen potential correlates with TMB, which quantifies the total somatic mutations within a tumor genome. A higher TMB generally correlates with a greater likelihood of generating immunogenic neoantigens, making it a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI). Progress in high-throughput sequencing, bioinformatics, and immuno-peptidomics has significantly enhanced the accuracy of neoantigen prediction, including assessments of major histocompatibility complex (MHC) binding affinity and T-cell receptor recognition. Clinically, neoantigen-based therapies have shown efficacy in early trials, with strategies such as mRNA vaccines demonstrating synergy with ICI by boosting T-cell activation and overcoming immune suppression. Combining neoantigen-based therapies with chemotherapy and radiotherapy harnesses synergistic mechanisms to enhance efficacy, overcome resistance, and emerge as a pivotal oncology research focus. The integration of TMB into clinical practice has received regulatory approval as a biomarker for stratifying patients for ICI therapies. Furthermore, advanced methodologies like liquid biopsy and single-cell technologies have streamlined TMB measurement, improving its predictive value for personalized immunotherapy. Collectively, neoantigens and TMB have optimized the evolution of precision immuno-oncology by providing frameworks that maximize therapeutic efficacy, overcome resistance mechanisms, and advance durable cancer remission.​.

Keywords: Clinical trials; Immunotherapy; Liquid biopsy; Tumor mutational burden; Tumor neoantigens.

Fig. 1

Milestone events of neoantigen, TMB and cancer immunotherapy. The breakthrough in neoantigen or TMB, the major achievement of cancer immunotherapy and their combination events were reviewed retrospectively. CTLA-4: cytotoxic T-lymphocyte-associated protein 4, FDA: Food and Drug Administration, NCCN: National Comprehensive Cancer Network, NSCLC: non-small cell lung cancer, PD-1: programmed cell death-1, PFS: progression-free survival, TMB: tumor mutational burden, WES: whole-exome sequencing, WGS: whole-genome sequencing. Created with BioRender.com

Fig. 2

The interrelationship between neoantigen, TMB and cancer immunotherapy. Neoantigens are derived from non-synonymous somatic mutations, leading to the production of novel or altered proteins that can be recognized as foreign by the immune system. When recognizing these neoantigens, the immune system triggers an anti-tumor immune response which represent personalized antigenic targets that can be exploited for targeted immunotherapy. On another hand, TMB quantifies the total number of somatic non-synonymous mutations within a tumor's genome. Higher mutational load suggests a greater likelihood of presenting a broader array of neoantigens, thereby providing a broad estimation of the neoantigen potential within a tumor. As a result, specific neoantigens offer a more targeted approach, while TMB serves as a predictive biomarker gauging the overall immunogenic potential of a tumor. Created with BioRender.com

Fig. 3

Mechanisms underlying neoantigen-based immunotherapy. Recognition of neoantigen-MHC complexes by T cells triggers immune cascades that drive therapeutic responses. CTL are pivotal in this process, inducing tumor cell apoptosis via perforin and granzymes release. CD4⁺ helper T cells augment this response by secreting cytokines which enhance CTL activation and prolong effector functions within the TME. Combination therapies further exploit neoantigens to amplify T cell activity. Radiotherapy releases neoantigens by inducing immunogenic cell death. OV similarly enhance neoantigen exposure by lysing tumor cells and activating innate immune pathways. Neoantigen-based mRNA vaccines directly expand tumor-reactive T cell populations. When combined with ICI, these vaccines counteract immunosuppressive mechanisms such as PD-L1 upregulation and sustain T cell effector functions. MHC I: major histocompatibility complex I, PD-L1: programmed cell death ligand-1, TCR: T cell receptor. Created with BioRender.com

Fig. 4

Mechanisms of TMB in predicting immunotherapy response. The mechanisms of TMB in predicting immunotherapy response can be delineated into four interrelated processes: neoantigen generation, antigen presentation, immune recognition, and host immune competency. a. Elevated TMB increases the probability of immunogenic neoantigen generation, as coding-region mutations may produce altered peptides perceived as"non-self"by the immune system. b. Elevated TMB increases the probability of neoantigen-MHC binding with sufficient affinity for surface presentation. c. In TMB-high tumors, neoantigen diversity also increases the probability of TCR recognition. d. Host immune competency, governed by systemic and local factors, also determines the response efficacy of immunotherapy. MHC: major histocompatibility complex, TCR: T cell receptor, TMB: tumor mutational burden. Created with BioRender.com

Fig. 5

Detection of TMB in cancer immunotherapy. The primary detection methods of TMB are shown in figure. WES remains the gold standard for comprehensive TMB assessment. Emerging technologies overcome the limitations of WES, such as high costs and lengthy processing times. ctDNA: circulating tumor DNA, scDNA-seq: single-cell DNA sequencing, scRNA-seq: single-cell RNA sequencing, WES: whole-exome sequencing, WGS: whole-genome sequencing. Created with BioRender.com