Albumin uptake through FcRn promotes tumor-associated macrophage maturation and albumin-bound immunotherapy response.

Abstract

Serum albumin accumulates in tumors and is widely exploited for drug delivery, but its accumulation and function in nonmalignant cells are less understood. Here, we show that tumor-associated macrophages (TAMs) are the dominant nonmalignant albumin-accumulating population in mouse tumors and exhibit the highest per-cell uptake. Bone marrow chimeras and adoptive transfer established a myeloid-intrinsic role for the neonatal Fc receptor (FcRn) in macrophage albumin uptake and monocyte-to-TAM maturation. FcRn loss reduced the intratumoral TAM-to-monocyte ratio approximately 3-fold. Albumin deficiency partially phenocopied this defect in mice while retrospective clinical data linked lower albumin to fewer TAMs. Mechanistically, albumin engaged p62-Nrf2 signaling, and Nrf2 inhibition impaired albumin-driven macrophage maturation. Leveraging this, albumin conjugation prolonged STING-agonist circulation and improved antitumor efficacy versus free agonist in syngeneic tumors, with diminished activity after macrophage depletion or host FcRn deficiency. These findings identify albumin as an endogenous regulator of TAM maturation and provide a mechanistic basis for myeloid-directed immunotherapies.