Although immune checkpoint blockade (ICB) therapy has generated dramatic responses in certain cancer types, breast tumors are largely unresponsive. Epithelial-mesenchymal plasticity (EMP) leads to the assembly of an immunosuppressive tumor microenvironment and drives resistance of breast tumors to immunotherapies. Importantly, targeting CD73 completely sensitizes quasi-mesenchymal (qM) breast tumors to anti-CTLA4 ICB therapy. However, the mechanism(s) of sensitization remained unknown. We demonstrate that targeting CD73 in qM breast tumors sensitizes them to anti-CTLA4 ICB therapy in a CD4+ T cell-dependent manner. Moreover, EMP results in elevated expression of cancer cell-intrinsic CD73 in human triple-negative breast cancers. Given the ability of qM cancer cells to metastasize and resist multiple therapies, these findings can instruct the formation of translational strategies for the treatment of human breast cancers. These findings also bring to the forefront the attractive possibility of utilizing the phenotypic plasticity of cancer cells along with CD73 and CD4+ T cells as a predictive criterion for immunotherapy responsiveness.
Significance: EMP enables metastasis and drives resistance to multiple treatment regimens. Our work underscores the possibility of utilizing CD4+ T cells, CD73, and cancer plasticity as predictive criteria for responsiveness to immunotherapy.
©2026 The Authors; Published by the American Association for Cancer Research.