Dampened NK inflammatory signaling and CD8⁺ T cell exhaustion precedes early relapse after posttransplant cyclophosphamide allogeneic BMT. The transcriptional landscape of NK cells CD8⁺ T cells in haploidentical alloBMT suggests development of effector function paralysis in relapse. Experimental workflow schema (A) and flow cytometry sort strategy (B) are shown. (C) Gene set enrichment analyses identified loss of inflammatory signatures in NK cells isolated from haplo alloBMT recipients who relapsed, with a dominant effect on TNF-α signaling. Analyses were performed using GSEA and hallmark dataset from the MSigDb (relapse n = 5; relapse-free n = 8). (D) Emergence of transcriptional exhaustion in haplo alloBMT CD8⁺ T cells also proceeded primary disease relapse. Custom GSEAs were performed using deposited datasets defining transcriptional hallmarks of functional T cell subsets. Subsequent development of disease relapse was positively associated with the acquisition of exhaustion and progressive loss of naïve CD8⁺ T cell phenotypes, suggesting impaired immune reconstitution (relapse n = 5; relapse-free n = 5).