PFKFB3 drives hepatocellular carcinoma growth and radiotherapy resistance under matrix mechanical forces

Abstract This commentary discusses the important study by Wang et al. on how tumor matrix stiffness drives radiotherapy resistance in hepatocellular carcinoma (HCC). The key breakthrough of this research lies in the discovery that the metabolic enzyme PFKFB3 undergoes nuclear translocation under mechanical stimulation and directly binds to the DNA repair protein Ku70. These findings not only highlight the contribution of matrix rigidity in the tumor microenvironment to HCC growth and DNA damage repair but also reveal a previously unrecognized non‐metabolic function of PFKFB3, thereby extending its functional scope from classical glycolytic regulation to direct maintenance of genomic stability. In our view, this discovery holds significant paradigm‐shifting importance, enriching the understanding of mechanical signaling in tumor biology and providing a mechanistic explanation for the adaptive survival of tumors.