Exosomal PKM2: A Noninvasive Diagnostic Marker Linking Macrophage Metabolic Reprogramming to Gastric Cancer Pathogenesis

Abstract

Tumor-derived exosomes (TDEs) have emerged as vital biomarkers of multiple cancers. However, the diagnostic and stage-predicting effects of exosomal pyruvate kinase isoenzyme type M2 (PKM2) in peripheral blood and its mechanism in promoting gastric cancer (GC) remain unclear. Here, we analyzed plasma exosomal PKM2 in 216 blood samples collected from GC patients and healthy donors (HD). The area under the curve (AUC) of plasma exosomal PKM2 demonstrated superior performance in early GC diagnosis compared with that of widely used clinical biomarkers. Kaplan–Meier analysis revealed that high exosomal PKM2 expression was associated with poor prognosis in patients with GC (HR = 1.623, p = 0.029). Single-cell transcriptome sequencing analysis showed that PKM2 was enriched in tumor-associated macrophages (TAM). We further confirmed that the polarization of TAM to the pro-tumoral M2 phenotype induced by exosomal PKM2 promoted the proliferation, migration, and invasion of GC cells. Mechanistically, exosomal PKM2 enhanced lipid synthesis in TAM by inhibiting SCAP polyubiquitination, which triggered the nuclear accumulation of SREBP1, thereby upregulating fatty acid synthesis enzymes, such as FASN, ACACA, and ACLY. In conclusion, plasma exosomal PKM2 is a promising novel biomarker for the clinical diagnosis of GC. Importantly, exosomal PKM2 shapes the tumor microenvironment by activating the SREBP1-related lipid synthesis pathway in macrophages, thereby contributing to GC development.