Intratumoral heterogeneity in cancer progression and response to immunotherapy

Nat Med. 2021 Feb;27(2):212-224. doi: 10.1038/s41591-021-01233-9. Epub 2021 Feb 11.


Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors. The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components. Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Genetic Heterogeneity*
  • Humans
  • Immunologic Factors / genetics*
  • Immunotherapy
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology


  • Immunologic Factors