Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm

Pediatric solid organ and hematopoietic stem cell transplant recipients paradoxically experience accelerated immune aging despite chronological youth, establishing a paradigm with profound implications for cancer risk and long-term outcomes. This comprehensive review synthesizes current evidence demonstrating how transplantation-related factors, anti-thymocyte globulin-mediated T cell depletion, cytomegalovirus reactivation, chronic immunosuppression, and thymic dysfunction, induce premature immunosenescent phenotypes. These processes converge to generate T cell populations exhibiting CD28 loss, killer cell lectin-like receptor G1 positivity, telomere attrition, and functional exhaustion characteristic of elderly individuals. Concurrently, inflammaging pathways and senescence-associated secretory phenotypes establish pro-tumorigenic microenvironments. Consequently, pediatric recipients demonstrate 4- to 20-fold elevated cancer incidence, with standardized incidence ratios for post-transplant lymphoproliferative disease exceeding 200 in some cohorts. Beyond hematological malignancies, significant increases in solid tumors suggest fundamental immunosurveillance failure. Emerging biomarkers including flow cytometric senescence panels, telomere length measurement, and epigenetic clocks enable personalized risk stratification. Therapeutic horizons encompass senolytic agents, checkpoint inhibitor modulation, thymic regeneration strategies, and metabolic interventions targeting aging pathways. This paradigm shift necessitates reconceptualizing pediatric transplantation through the aging lens, integrating precision medicine approaches that balance graft survival, immune competence preservation, and cancer prevention in this vulnerable population.