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Intratumor heterogeneity and anti-tumor immunity shape one another bidirectionally.

Over the last decade, it has become clear that the genomic landscapes of tumors profoundly impact their immunogenicity and how tumor cells interact with immune cells. Whereas past discoveries mainly focused on the interplay between tumor immunogenicity and tumor mutational burden (TMB), under the assumption that a higher mutation load would give rise to a better patient response to immune checkpoint blockade (ICB) therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the anti-tumor response and the nature of the tumor microenvironment. In this Review, we define TMB vs. ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex crosstalk between TMB, ITH and anti-tumor immunity in human cancers and in-vivo models, and discuss the mutual influence of ITH and immunity - how the anti-tumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the anti-tumor response.