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<p>Breast cancer is the foremost cause of cancer-related death in women globally, and taxane-anthracycline (TA) combination regimens represent standard frontline chemotherapy. Although widely administered, the pathological complete response rate to TA therapy is less than 30%, and chemoresistance remains a major barrier to effective disease control, frequently leading to relapse and poor survival. Both metabolic reprogramming and tumor microenvironmental remodeling are closely associated with treatment failure, yet how they interact to drive TA resistance remains largely unclear. Here we show that phosphofructokinase platelet (PFKP), a key glycolytic enzyme, is highly expressed in breast cancer. PFKP drives glycolysis and promotes CD133<sup>+</sup> cancer stem-like cells (CSLCs) that are inherently TA-resistant. Moreover, PFKP-overexpressing cancer cells stimulate cancer-associated fibroblasts (CAFs), which in turn augment CD133<sup>+</sup> CSLC formation via the CXCL16/CXCR6 axis, establishing a feedforward loop that reinforces chemoresistance. These results reveal a previously unappreciated mechanism by which a glycolytic enzyme in cancer cells orchestrates stromal crosstalk to sustain a chemotherapy-refractory niche. By identifying PFKP as a key driver and the PFKP–CSLC–CAF axis as an actionable target, our work moves the field beyond the traditional view of metabolic reprogramming as a cell-autonomous event. Disrupting this axis—for instance, by PFKP inhibition or CXCL16/CXCR6 blockade—may restore TA sensitivity in aggressive basal-type breast cancer, offering a promising strategy to improve long-term outcomes for hard-to-treat patients.</p>

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PFKP is required for chemoresistant phenotype of breast cancer through modulating the formation of CD133+ cancer stem like cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Kai Fang,
  • Yue Ma,
  • Lihua Li,
  • Yan Yue,
  • Hang Ruan,
  • Sidong Xiong

摘要

Breast cancer is the foremost cause of cancer-related death in women globally, and taxane-anthracycline (TA) combination regimens represent standard frontline chemotherapy. Although widely administered, the pathological complete response rate to TA therapy is less than 30%, and chemoresistance remains a major barrier to effective disease control, frequently leading to relapse and poor survival. Both metabolic reprogramming and tumor microenvironmental remodeling are closely associated with treatment failure, yet how they interact to drive TA resistance remains largely unclear. Here we show that phosphofructokinase platelet (PFKP), a key glycolytic enzyme, is highly expressed in breast cancer. PFKP drives glycolysis and promotes CD133+ cancer stem-like cells (CSLCs) that are inherently TA-resistant. Moreover, PFKP-overexpressing cancer cells stimulate cancer-associated fibroblasts (CAFs), which in turn augment CD133+ CSLC formation via the CXCL16/CXCR6 axis, establishing a feedforward loop that reinforces chemoresistance. These results reveal a previously unappreciated mechanism by which a glycolytic enzyme in cancer cells orchestrates stromal crosstalk to sustain a chemotherapy-refractory niche. By identifying PFKP as a key driver and the PFKP–CSLC–CAF axis as an actionable target, our work moves the field beyond the traditional view of metabolic reprogramming as a cell-autonomous event. Disrupting this axis—for instance, by PFKP inhibition or CXCL16/CXCR6 blockade—may restore TA sensitivity in aggressive basal-type breast cancer, offering a promising strategy to improve long-term outcomes for hard-to-treat patients.