Targeting the atypical chemokine receptor 2 ( <i>Ackr2</i> ) improves the benefit of anti-PD-1 immunotherapy in melanoma mouse model

Immune checkpoint blockade (ICB) therapies, such as anti-PD-1, have transformed cancer treatment, but many patients do not respond due to a non-inflammatory tumor microenvironment (TME). Here, we investigated the impact of targeting Atypical Chemokine Receptor 2 (<i>ACKR2</i>), which scavenges key chemokines involved in immune cell recruitment, on the improvement of anti-PD-1-based therapy. In a melanoma mouse model, we demonstrated that <i>Ackr2</i> inhibition increases the release of proinflammatory chemokines CCL5 and CXCL10 and enhances the infiltration of NK cells, activated CD8+ and CD4+ effector T cells while reducing regulatory T cells (Tregs) in the TME. Targeting <i>Ackr2</i> led to tumor growth inhibition, improved survival, and enhanced response to anti-PD-1 therapy. In BRAF- and NRAS-mutant melanoma patients, low <i>ACKR2</i> expression or high CCL5/CXCL10 levels correlated with improved survival and higher CD8+ T cell markers. Targeting <i>ACKR2</i> represents a promising approach for developing combination therapies, particularly for 'cold' ICB resistant tumors.