Basophils inhibit early lung metastasis by suppressing regulatory T cells

Abstract Basophils are rare cells best known for their role in allergy but their contribution to cancer remains poorly understood. Here, we found that basophils suppress early lung metastatic seeding in mice by enhancing antitumor CD8 + T cell immunity through inhibition of regulatory T (T reg ) cells. Basophils restrain T reg cells through two complementary mechanisms: mast cell protease 8-mediated cleavage of interleukin-2 receptor α and histamine-mediated activation of the histamine H1 receptor (HRH1). HRH1 blockade with loratadine abolished T reg cell suppression and accelerated metastatic seeding in mice. In a prospective double-blind crossover trial of loratadine versus placebo enrolling 40 healthy volunteers ( IRCT20170608034390N14 ), circulating T reg cell frequency (primary outcome) increased following loratadine. Higher blood basophil counts predicted improved survival across human cancers and integrative multiomic analyses identified conserved quiescent (B0) and tumor-associated (B1) basophil states, with B0 predicting favorable outcomes. These findings identify basophils as regulators of early metastatic progression and highlight the basophil–T reg cell axis as a potential therapeutic target.