DCBLD2 promotes perivascular anti-tumor immune deprivation by educating SPP1+ pro-angiogenic macrophages

The crosstalk between tumor vasculature and immune microenvironment underpins the anti-tumor effect of anti-angiogenic therapy (AAT) combined with immunotherapy. However, the efficacy improved by AAT in the above combination therapy is limited and its adverse effects are concerning. Integrated transcriptome and surfaceome data identified DCBLD2 as a bipotent molecule on tumor cells as a trigger for abnormal tumor vascular-immune interactions. Dcbld2 overexpression accelerated tumor growth through tumor-associated macrophages (TAMs) in preclinical mouse models. Mechanically, DCBLD2 domesticates SPP1+ pro-angiogenic TAMs through ALDH1A3-RXRG-PLK1 axis, constructing TAMs-coated vascular niches that sequester CD8+ T cell infiltration. DCBLD2 expression levels predicted the efficacy of traditional AAT in our lung cancer patient cohorts. Targeting DCBLD2 or ALDH1A3 combined with PD-1 antibody outperformed traditional AAT and immunotherapy combination. Our study identifies DCBLD2 on tumor cells as a checkpoint in abnormal vascular-immune crosstalk, offering a promising target to amplify the potency of vascular normalization and immune activation.