CD1d remodels the tumor-infiltrating myeloid populations controlling antitumor immunity.

Myeloid cells play crucial roles in cancer progression, influencing tumor growth, metastasis, and response to immunotherapy. The mechanisms shaping their diverse functions in the tumors remain poorly understood and may offer therapeutic opportunities. Here, we identify the lipid-presenting molecule CD1d as a regulator of tumor progression and myeloid heterogeneity in the tumor microenvironment. Using several mouse models of breast cancer, we demonstrate that genetic deletion or antibody-mediated targeting of CD1d leads to reduced tumor growth, altered immune infiltration, and improved efficacy of anti-PD-1 immunotherapy. Specifically, CD1d targeting reshapes the intratumoral myeloid compartment, enhancing proinflammatory programs and resulting in accumulation of inflammatory monocytes. The CD1d-dependent control of myeloid cell functional differentiation is cell-intrinsic and conserved in human and mouse. Through single-cell RNA sequencing, we define the transcriptional landscape associated with CD1d deficiency and derive a gene signature that correlates with clinical outcomes and response to immunotherapy in breast cancer patients. Thus, CD1d could provide a potential target to alter tumor-infiltrating myeloid populations and enhance immunotherapy responses.