Revisiting of Cancer Immunotherapy: Insight from the Dialogue between Glycolysis and PD-1/PD-L1 Axis in the Tumor Microenvironment

The interplay between metabolic pathways and immune escape has emerged as a captivating research area in oncobiology. Among these, the Warburg effect stands out as a hallmark metabolic reprogramming in cancer, characterized by elevated glucose utilization and excessive lactic acid production through anaerobic glycolysis. Key glycolytic enzymes not only fulfill the bioenergetic demands of cancer cells but also exhibit moonlighting roles, including regulation of epigenetic modifications, protein kinase activity, and immune escape mechanisms, thereby reshaping the tumor microenvironment. Tumor-specific vascular architecture facilitates lactate accumulation, which drives tumor progression by impairing immune cell function and acting as a signaling molecule to recruit immunosuppressive cells and modulate immune checkpoint pathways. The PD-1/PD-L1 co-stimulatory pathway plays a crucial role in negatively modulating the activation, proliferation, and cytokine secretion by T-lymphocytes. This review primarily focuses on elucidating the regulation and mechanisms underlying PD-1/PD-L1 signaling axis during glycolysis in tumor cells as well as surrounding cells. In the era of precision medicine, there is a particular interest in leveraging ¹⁸F-FDG PET/CT imaging as a valuable tool to assess PD-L1 expression status for more targeted therapeutic interventions. Additionally, the development of natural compounds capable of modulating metabolism opens new avenues for metabolism-based immunotherapy, though further studies are required to validate their in vivo efficacy.