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Tumor Mutational Burden Shapes Success and Resistance in Cancer Immunotherapy

Guim Aguadé-Gorgorió1

  • 1ISEM, Université de Montpellier, CNRS, Montpellier, France.

Journal of Theoretical Biology
|February 26, 2026
PubMed

Insights

Cancer mutations impact immunotherapy success. A new model shows how tumors evolve resistance through silent clones or immune evasion, limiting treatment effectiveness in many patients.

Area of Science:

  • Evolutionary biology
  • Cancer immunology
  • Computational oncology

Background:

  • Immune checkpoint blockade has revolutionized cancer therapy but shows limited durable responses.
  • Tumor mutational burden (TMB) is crucial for immunotherapy outcomes, yet its role is complex.
  • Tumors can develop resistance via immune evasion or neoantigen editing.

Purpose of the Study:

  • To model the eco-evolutionary dynamics of oncogenic and immunogenic mutations.
  • To understand how tumor mutational burden influences cancer cell replication and immune recognition.
  • To identify mechanisms of innate and acquired resistance to cancer immunotherapy.

Main Methods:

  • Developed a minimal eco-evolutionary model of cancer cell replication.
  • Analyzed trade-offs between oncogenic and immunogenic mutations.
  • Simulated tumor evolution under immune pressure.

Main Results:

  • Identified an evolutionary bimodal regime where silent and mutationally active tumors coexist.
  • Demonstrated how high TMB can harbor pre-existing resistant clones.
  • Showed that immune pressure drives immunoediting and selection for reduced antigenicity.

Conclusions:

  • Tumor mutational burden plays a dual role in immunotherapy response and resistance.
  • Eco-evolutionary dynamics explain key resistance mechanisms like pre-existing resistance and immunoediting.
  • Understanding these evolutionary strategies is vital for improving cancer immunotherapy efficacy.
Keywords:
Cancer evolutionImmunotherapy resistanceIntra-tumor heterogeneityMathematical oncologyTumor mutational burden

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