Current research status of the reverse Warburg effect in cancer-associated fibroblasts of solid tumors.

The malignant progression of solid tumors is not dictated solely by the intrinsic properties of cancer cells. Instead, dynamic interactions with cancer-associated fibroblasts (CAFs) are increasingly being acknowledged as critical driving forces. These interactions arise from sustained signaling cues within the tumor microenvironment, which elicit phenotypic transitions and metabolic reprogramming in CAFs, thereby initiating a distinct metabolic state, known as the Reverse Warburg Effect. In contrast to the canonical aerobic glycolysis observed in tumor cells, CAFs exhibit markedly elevated glycolytic activity in this metabolic state and generate large quantities of lactate and other metabolites. These products are subsequently internalized and efficiently utilized by the adjacent tumor cells, thereby providing sustained support for energy generation and anabolic metabolism. Monocarboxylate transporters (MCTs) function as central metabolic nodes in this crosstalk, facilitating lactate shuttling between CAFs and cancer cells and positioning the Reverse Warburg Effect as an integral component of tumor metabolic reprogramming. Beyond its role as an energy source, CAF-derived lactate actively modulates the immunosuppressive microenvironment and triggers epigenetic regulatory changes, which together reinforce tumor progression and therapeutic resistance emergence. Accordingly, strategies aimed at targeting CAF metabolic remodeling, disrupting the lactate shuttle axis, or reversing CAF-driven immunosuppressive phenotypes are increasingly regarded as promising strategies to reprogram the tumor microenvironment and improve the efficacy of current anticancer therapies.