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 therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the antitumor response and the nature of the tumor microenvironment. In this review, we define TMB versus ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex cross-talk between TMB, ITH, and antitumor immunity in human cancers and in vivo models, and discuss the mutual influence of ITH and immunity-how the antitumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the antitumor response.
©2022 The Authors; Published by the American Association for Cancer Research.