IL-6R blockade with tocilizumab disrupts pericyte– and tumor cell–driven IL-6/STAT3 signaling, enhancing docetaxel efficacy in ER+ breast cancer

Metastatic breast cancer is a global health concern with a persistently low five-year survival rate. Taxane microtubule stabilizers, including docetaxel (DTX), are the standard of care, with a majority of estrogen receptor-postive (ER+) breast cancer patients ultimately developing cancer relapse and progression. Pericytes, vascular cells within the tumor microenvironment, and their role in promoting pro-survival remain understudied. Inflammatory cytokines such as interleukin 6 (IL-6) are known to drive and contribute to drug resistance via activation of the pro-survival JAK/STAT pathway. We found that DTX induced IL-6 secretion of pericytes by at least two-fold compared to vehicle-treated controls in vitro . All tested breast cancer cell lines expressed subunits of the IL-6 receptor (IL-6R) complex, indicating their capacity to respond to JAK/STAT signaling. Conditioned media from DTX-treated pericytes activated STAT3 in ER+ breast cancer cells to levels comparable to recombinant IL-6. Pharmacologic blockade of IL-6 signaling with the IL-6R inhibitor, tocilizumab, reduced DTX-induced STAT3 activation in vitro. Combined treatment with tocilizumab and DTX synergistically suppressed the growth of zero-passage patient-derived ER+ breast cancer organoids expressing intact IL-6 signaling. Together, our findings suggest that combining DTX with tocilizumab may revert DTX-induced pro-survival in ER+ breast cancer patients by inhibiting IL-6-mediated activation of the STAT3 pathway.