Hypoxic preconditioning promotes recipient monocyte adaptation to improve heart transplant outcomes

Abstract Acute heart allograft rejection remains a major barrier to long-term transplant survival, yet the mechanisms by which environmental factors influence recipient alloimmunity remain poorly understood. Clinical observations have suggested improved transplant outcomes at higher elevations, but the underlying biology has not been established. Here, using a murine heterotopic heart transplantation model, we demonstrate that recipient, but not donor, hypoxic preconditioning significantly prolongs heart allograft survival, and that pre-transplant hypoxic exposure alone is sufficient to confer this benefit. Single-cell RNA sequencing of recipient peripheral blood mononuclear cells revealed that chronic hypoxia suppresses antigen presentation programs while enriching tolerance-associated transcriptional signatures and remodels the circulating myeloid compartment toward non-classical monocytes. Pharmacologic inhibition of hypoxia-inducible factor 2α (HIF2α) with belzutifan abolished the survival advantage conferred by recipient hypoxia, demonstrating that HIF2 activity is required for this protective immune adaptation. Together, these findings identify chronic recipient hypoxic conditioning as a previously unrecognized regulator of innate immune remodeling and suggest that therapeutically promoting a hypoxia-induced tolerogenic monocyte state may represent a strategy to improve heart transplant outcomes.