Single-cell and spatial transcriptomics identify PGK1-sensitized hypoxia macrophages as a therapeutic target to
Xiuwei Yan1, Jiahe Hu1, Xuyan Han1
1Cancer Center, Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
Abstract:
Photodynamic therapy (PDT) resistance in glioma is primarily driven by therapy-induced hypoxia, yet the specific role of hypoxic tumor-associated macrophages (Hypoxia-TAM) remains unclear. By integrating single-cell and spatial transcriptomics of paired Pre-PDT and recurrent post-PDT (RP-PDT) human glioma samples with functional assays, we identified Hypoxia-TAM as critical mediators of resistance. These cells underwent significant glycolytic reprogramming, orchestrated by phosphoglycerate kinase 1 (PGK1). We demonstrated that PGK1 phosphorylates pyruvate dehydrogenase kinase 1 (PDHK1), reinforcing a glycolytic state. Furthermore, PGK1-driven Hypoxia-TAM promoted glioma progression through an osteopontin (SPP1)-CD44 paracrine axis, a interaction confirmed by co-immunoprecipitation in RP-PDT samples. Genetic targeting of either PGK1 or SPP1 restored oxidative metabolism in Hypoxia-TAM, suppressed glioma invasiveness, and synergized with PDT to delay tumor growth and prolong survival in orthotopic models. Our findings reveal a PGK1-centered metabolic-paracrine axis in Hypoxia-TAM that drives PDT resistance, nominating this pathway as a promising therapeutic target for glioma.
