The mechanism of PKM2/HIF-1α axis polarizing TAMs by upregulating glucose-serine metabolism to promote melanoma progression

Background Melanoma is the most aggressive skin cancer. Tumor-associated macrophages (TAMs) promote melanoma progression through polarization, however, whether glucose-serine metabolism regulates TAMs polarization and the specific regulatory mechanism remain unclear. Methods Immunohistochemistry (IHC) was used to detect the infiltration of M2-type TAMs in melanoma tumor tissues; bioinformatics analysis was employed to identify HIF-1α, a key gene regulating glucose metabolism and polarization of TAMs; in vivo and in vitro experiments were conducted to determine whether HIF-1α promotes melanoma progression by regulating TAMs polarization and to explore the regulatory mechanism of HIF-1α on glucose-serine metabolism and polarization in melanoma TAMs; Co-IP, immunofluorescence, and functional rescue experiments were used to verify the upstream regulatory factors of HIF-1α. Results M2-type TAMs were highly enriched in melanoma tumor tissues and closely associated with tumor progression and poor prognosis. Single-cell sequencing data of melanoma suggested that HIF-1α is a key gene regulating glucose metabolism and polarization in TAMs. In vivo and in vitro experimental results demonstrated that HIF-1α upregulated glucose–serine metabolism in melanoma TAMs, thereby driving their polarization toward the M2 phenotype and consequently promoting tumor progression. PKM2 acted as an upstream regulatory factor of HIF-1α, and the PKM2/HIF-1α axis upregulated glucose-serine metabolism in TAMs to induce polarization. Additionally, a self-reinforcing circuit regulatory relationship among PKM2/HIF-1α/serine was identified within melanoma TAMs. Conclusions Our study reveals that the PKM2/HIF-1α axis upregulates glucose–serine metabolism to induce M2 polarization of TAMs and drive melanoma progression. Targeting this metabolic axis thus holds promise as a novel therapeutic strategy for melanoma patients.