ACKR3 Establishes a Squamous-Restricted Immune Checkpoint Axis in Lung Squamous Cell Carcinoma.

ACKR3 acts as a squamous-enriched immune checkpoint regulator that restrains tumor growth and modulates immune microenvironment in lung squamous cell carcinoma.

• Why it matters: LUSC has limited targeted therapies and unclear immune dependencies, making it crucial to identify new immune regulatory mechanisms to improve treatment options.
• What they did: The study used human datasets, mouse models, and organoid systems to show that loss of ACKR3 accelerates tumor growth, reduces CD8+ T cell infiltration, and increases T cell exhaustion by activating the MIF-CD74-PD-L1 axis.
• The result: Targeting ACKR3 with a PD-L1 degrader enhanced antitumor effects, especially with chemotherapy, suggesting ACKR3-directed PD-L1 degradation as a tumor-selective therapy for LUSC.