β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells

β-adrenergic signaling has been suggested to promote tumor growth, and β-blockers are being evaluated for repurposing for cancer treatment. Here, we identify a novel β-adrenergic signaling axis involved in metastasis formation. We show that the β-blocker propranolol has strong anti-metastatic activity in multiple murine models, with this effect being completely dependent on CD4+ T cells. Notably, the anti-metastatic effect of propranolol is unaffected by depletion of NK or CD8+ T cells. Propranolol induces a Th1-polarized and cytotoxic CD4+ T cell response, which requires MHC class II expression by cancer cells for full efficacy. This effect of propranolol is driven by systemic changes in the monocyte compartment rather than direct action on CD4+ T cells. Specifically, propranolol decreases the number of inflammatory monocytes and skews remaining monocytes towards an antigen-presenting phenotype. Propranolol treatment synergizes with anti-CTLA-4 therapy to further enhance CD4+ T cell infiltration and control metastasis. This study identifies β-adrenergic signaling as a key driver of metastasis and shows that the β-blocker propranolol reduces metastasis through monocyte-dependent activation of cytotoxic CD4+ T cells.