HLA class I molecules are key in tumor recognition and T cell–mediated elimination. Loss of tumor HLA class I expression with different underlying molecular defects results in reduced antigen presentation and facilitates cancer immune evasion. It is also linked to significant changes in tumor microenvironment and tissue architecture. In this review, we summarize the current advances and future perspectives in the understanding of the mechanisms of MHC/HLA class I alterations during the natural history of tumor progression from a primary lesion to distant metastases. We also focus on recent clinical and experimental data demonstrating that lack of response to cancer immunotherapy frequently depends on the molecular nature of tumor HLA class I aberrations. Finally, we highlight the relevance of detecting and correcting the absence of tumor HLA expression to improve immunotherapy protocols.

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