Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer

Significance Although immune checkpoint blockade (ICB) along with nab-paclitaxel has increased progression-free survival in triple-negative breast cancer patients, a large fraction of metastatic breast cancer (mBC) patients do not benefit from ICBs. The presence of a fibrotic tumor microenvironment can suppress the immune response to cancer. Here we found fibrosis and immunosuppression in both primary and metastatic breast cancer lesions. We show that targeting CXCR4/CXCL12 signaling, using plerixafor, an Food and Drug Administration-approved drug, reduces fibrosis, alleviates immunosuppression, and significantly enhances the efficacy of immune checkpoint blockers in preclinical models of mBC. Our findings provide a deeper understanding of mechanisms by which desmoplasia promotes immunosuppression in mBC and suggest a clinically translatable approach that can be combined with immunotherapy in patients to enhance therapeutic response.