The study investigates the role of tumor-specific mutant antigens (TSMA) in checkpoint blockade cancer immunotherapy. Using genomics and bioinformatics approaches, the researchers identified TSMA as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy in mice with growing sarcomas. They found that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes were effective in inducing tumor rejection, comparable to checkpoint blockade immunotherapy. The study also revealed that TSMA-specific T cells are present in progressively growing tumors but are reactivated following checkpoint blockade therapy, displaying treatment-specific transcriptional profiles. These findings highlight the importance of TSMA in checkpoint blockade therapy and their potential for developing personalized cancer vaccines. Additionally, the study provides insights into the molecular changes occurring within tumor antigen-specific T cells following checkpoint blockade, suggesting that different therapies may achieve tumor eradication through distinct mechanisms.The study investigates the role of tumor-specific mutant antigens (TSMA) in checkpoint blockade cancer immunotherapy. Using genomics and bioinformatics approaches, the researchers identified TSMA as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy in mice with growing sarcomas. They found that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes were effective in inducing tumor rejection, comparable to checkpoint blockade immunotherapy. The study also revealed that TSMA-specific T cells are present in progressively growing tumors but are reactivated following checkpoint blockade therapy, displaying treatment-specific transcriptional profiles. These findings highlight the importance of TSMA in checkpoint blockade therapy and their potential for developing personalized cancer vaccines. Additionally, the study provides insights into the molecular changes occurring within tumor antigen-specific T cells following checkpoint blockade, suggesting that different therapies may achieve tumor eradication through distinct mechanisms.