This study investigates the mechanisms of cancer immunoediting, a process where the immune system controls tumor growth and shape. Using highly immunogenic methylcholanthrene-induced sarcomas from immunodeficient mice, the authors identified a T cell-dependent mechanism of immunoediting. They found that the strong immunogenicity of these tumors is due to the expression of highly antigenic mutant proteins, specifically mutant spectrin-β2. This antigen was identified through in silico prediction and validated by conventional antigen expression cloning. The study demonstrates that the outgrowth of tumor cells lacking strong antigens, such as those with mutant spectrin-β2, is a key mechanism of cancer immunoediting. This mechanism likely also applies to other types of escape tumors, such as those with inactivating mutations in antigen presentation genes. The findings highlight the potential of using genomics to identify tumor-specific antigens for immunotherapy.This study investigates the mechanisms of cancer immunoediting, a process where the immune system controls tumor growth and shape. Using highly immunogenic methylcholanthrene-induced sarcomas from immunodeficient mice, the authors identified a T cell-dependent mechanism of immunoediting. They found that the strong immunogenicity of these tumors is due to the expression of highly antigenic mutant proteins, specifically mutant spectrin-β2. This antigen was identified through in silico prediction and validated by conventional antigen expression cloning. The study demonstrates that the outgrowth of tumor cells lacking strong antigens, such as those with mutant spectrin-β2, is a key mechanism of cancer immunoediting. This mechanism likely also applies to other types of escape tumors, such as those with inactivating mutations in antigen presentation genes. The findings highlight the potential of using genomics to identify tumor-specific antigens for immunotherapy.