A significant risk for transplant recipients is the development of tumors. In general, some but not all malignancies are more frequent in transplant hosts due to chronic immunosuppression caused by a compromised immune surveillance. Of additional relevance, checkpoint blockade therapies (CBT) to treat malignancies can also drive transplant rejection. In a recent study published in Nature Communications, Dunlap et al. reported a case study of a patient who experienced kidney allograft rejection following CBT for melanoma. The foresight of longitudinally preserving donor splenocytes, blood samples, and graft biopsies in addition to tumor and metastatic lymph nodes enabled paired single-cell RNA-seq (scRNA-seq) and TCR-sequencing (TCR-seq) and subsequent tracking of alloreactive T cells before and after CBT. This revealed an enrichment of alloreactive TCRs in the kidney transplant post-CBT but not the tumor. In addition, this approach helped identify an alloreactive CD8+ T cell subset with a unique transcriptional profile. This study illustrates possible advances in personalized medicine and highlights a transcriptional signature that may serve as a prospective biomarker of rejection.