Unraveling TIME: CD8+ T cell– and CXCL11-driven endocrine resistance in breast cancer

A major unmet need in estrogen receptor-positive (ER+) breast cancer is understanding the mechanisms that underlie resistance to endocrine therapy. Although accumulating evidence suggests an association between the tumor immune microenvironment (TIME) and endocrine response, the specific role of the TIME in mediating endocrine resistance remains unclear. In this issue of the JCI, Napolitano et al. analyzed tumor biopsies from patients with ER+ breast cancer and reported that endocrine-resistant tumors exhibited heightened CD8+ T cell infiltration and activation of the CXCL11 - CXCR3/-7 axis. Spatial and coculture analyses of these tumors demonstrated that the CD8+ T cell-associated chemokine CXCL11 drove estrogen-independent tumor growth. These findings identify an immune-mediated mechanism of endocrine resistance in breast cancer and identify CXCL11 as a potential biomarker and therapeutic vulnerability.