Phenotype

Pathology

Tumor microenvironment

Immunotherapy

Disease

Biology

Gene

Somatic evolution in cancer

Cancer

Immunology

Tumour heterogeneity

Tumor progression

Genetic heterogeneity

Genetics

Medicine

Nature Medicine

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. The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes.

Intratumoral heterogeneity in cancer progression and response to immunotherapy