A study published in *Nature* (2014) explores how checkpoint blockade immunotherapy targets tumor-specific mutant antigens. The research identifies tumor-specific mutant antigens (TSMA) as key targets for therapies that block CTLA-4 and PD-1, which are critical for immune suppression in cancer. Using genomics and bioinformatics, the study shows that TSMA are major targets for T cells activated by checkpoint blockade, and that vaccines based on these antigens can induce tumor rejection as effectively as the therapy itself. The study used two MCA sarcoma cell lines, d42m1-T3 and F244, to investigate how checkpoint blockade therapy affects tumor rejection. Both lines were rejected in wild-type mice treated with anti-PD-1 and/or anti-CTLA-4. The rejection was immunological, as it required CD4+ and CD8+ T cells and IFN-γ, and was not observed in mice lacking T, B, or NKT cells. The study also showed that the rejection induced a memory response that protected mice against rechallenge. Using genomics, the researchers identified TSMA responsible for the rejection of d42m1-T3 tumors. They found that two mutant epitopes, A506T in Alg8 and G1254V in Lama4, were strongly bound by H-2Kb and were recognized by CD8+ T cells. These epitopes were validated using tetramer staining and co-culture experiments with splenocytes. The study also showed that these epitopes were present in the tumor-infiltrating lymphocytes (TILs) of mice treated with checkpoint blockade therapy. Further analysis revealed that these TSMA were not only targets of checkpoint blockade therapy but could also be used to develop personalized vaccines. The study also showed that checkpoint blockade therapy led to the reactivation of T cells specific for these antigens, which displayed treatment-specific transcriptional profiles. These T cells were capable of mediating tumor rejection. The study also compared the effects of checkpoint blockade therapy with therapeutic vaccines based on TSMA. It showed that vaccines composed of these antigens were effective in inducing tumor rejection, comparable to checkpoint blockade therapy. The study also demonstrated that TSMA could be used to identify tumor-specific T cells as biomarkers of successful anti-tumor responses. The findings suggest that checkpoint blockade therapy amplifies pre-existing anti-tumor T cell responses and that dual blockade of CTLA-4 and PD-1 is particularly effective in promoting enhanced anti-tumor effector functions. The study also highlights the potential of TSMA-based vaccines in cancer immunotherapy, as they can target multiple antigens and provide better coverage of the tumor cell population. The study provides experimental support for clinical observations that checkpoint blockade therapy can be effective in treating various cancers.A study published in *Nature* (2014) explores how checkpoint blockade immunotherapy targets tumor-specific mutant antigens. The research identifies tumor-specific mutant antigens (TSMA) as key targets for therapies that block CTLA-4 and PD-1, which are critical for immune suppression in cancer. Using genomics and bioinformatics, the study shows that TSMA are major targets for T cells activated by checkpoint blockade, and that vaccines based on these antigens can induce tumor rejection as effectively as the therapy itself. The study used two MCA sarcoma cell lines, d42m1-T3 and F244, to investigate how checkpoint blockade therapy affects tumor rejection. Both lines were rejected in wild-type mice treated with anti-PD-1 and/or anti-CTLA-4. The rejection was immunological, as it required CD4+ and CD8+ T cells and IFN-γ, and was not observed in mice lacking T, B, or NKT cells. The study also showed that the rejection induced a memory response that protected mice against rechallenge. Using genomics, the researchers identified TSMA responsible for the rejection of d42m1-T3 tumors. They found that two mutant epitopes, A506T in Alg8 and G1254V in Lama4, were strongly bound by H-2Kb and were recognized by CD8+ T cells. These epitopes were validated using tetramer staining and co-culture experiments with splenocytes. The study also showed that these epitopes were present in the tumor-infiltrating lymphocytes (TILs) of mice treated with checkpoint blockade therapy. Further analysis revealed that these TSMA were not only targets of checkpoint blockade therapy but could also be used to develop personalized vaccines. The study also showed that checkpoint blockade therapy led to the reactivation of T cells specific for these antigens, which displayed treatment-specific transcriptional profiles. These T cells were capable of mediating tumor rejection. The study also compared the effects of checkpoint blockade therapy with therapeutic vaccines based on TSMA. It showed that vaccines composed of these antigens were effective in inducing tumor rejection, comparable to checkpoint blockade therapy. The study also demonstrated that TSMA could be used to identify tumor-specific T cells as biomarkers of successful anti-tumor responses. The findings suggest that checkpoint blockade therapy amplifies pre-existing anti-tumor T cell responses and that dual blockade of CTLA-4 and PD-1 is particularly effective in promoting enhanced anti-tumor effector functions. The study also highlights the potential of TSMA-based vaccines in cancer immunotherapy, as they can target multiple antigens and provide better coverage of the tumor cell population. The study provides experimental support for clinical observations that checkpoint blockade therapy can be effective in treating various cancers.