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Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.<\/jats:p>","DOI":"10.1038\/s41467-024-45292-1","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T06:03:07Z","timestamp":1708495387000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Converging and evolving immuno-genomic routes toward immune escape in breast cancer"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9526-7450","authenticated-orcid":false,"given":"Juan","family":"Blanco-Heredia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-7275","authenticated-orcid":false,"given":"Carla 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L.D.M.A. is currently employed by BioNTech SE. H.H. is co-founder and shareholder of Omniscope, SAB member of Nanostring and MiRXES, and consultant to Moderna and Singularity. C.A.S. is a scientific associate of Dataomics Biotech. J.B.H. is currently affiliated with the\u00a0Marie-Jos\u00e9e and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.\u00a0J.S.R.-F. reports receiving personal\/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics, MultiplexDX, and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of AstraZeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the scope of this study. J.S.R.-F. is currently employed by AstraZeneca. B.W. reports research funding from Repare Therapeutics, outside the scope of the submitted work. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1302"}}