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

Lung squamous cell carcinoma (LUSC) is an aggressive subtype of non–small cell lung cancer with limited targeted therapeutic options and incompletely defined immune-regulatory dependencies. Here, we identified atypical chemokine receptor 3 (ACKR3) as a squamous-enriched regulator that restrains malignant progression in LUSC. Integrative analyses of human LUSC datasets, autochthonous genetically engineered mouse models, and ex vivo organoid systems showed that ACKR3 loss accelerated tumor growth and remodeled the immune microenvironment, marked by reduced CD8⁺ T cell infiltration and increased T cell exhaustion. Mechanistically, ACKR3 limited activation of the MIF–CD74–PD-L1 axis, thereby constraining tumor-cell PD-L1 expression and preserving antitumor immune surveillance. In preclinical LUSC models, treatment with the ACKR3-directed PD-L1 degrader KineTAC, a bispecific molecule that co-engages ACKR3 and PD-L1 to promote lysosomal degradation of PD-L1, enhanced antitumor efficacy, particularly in combination with chemotherapy. Together, these findings define ACKR3 as a squamous-associated immune checkpoint regulator and nominate ACKR3-directed PD-L1 degradation as a tumor-selective therapeutic strategy for LUSC.