CD147 at the crossroads of glycoprotein networks, metabolic reprogramming, and metastatic progression

Abstract

CD147 (also known as EMMPRIN or Basigin), a transmembrane glycoprotein of the immunoglobulin superfamily, functions as a pivotal regulator of tumor progression. It coordinates key oncogenic processes-including metabolic adaptation, chemoresistance, angiogenesis, and immune modulation-through an extensive network of protein-protein interactions. Metabolic reprogramming not only reshapes the intrinsic metabolic circuitry of tumor cells but also promotes the establishment of a pre-metastatic niche that facilitates metastatic seeding and outgrowth via dynamic metabolic crosstalk with immune and stromal components. Here, we review current evidence showing that CD147 mediates PMN formation by promoting immune evasion, metabolic adaptation, and stromal remodeling. Through the coordination with membrane-associated glycoproteins-including CD44, epidermal growth factor receptor (EGFR), integrins, CD280 (uPARAP/Endo180/MRC2), and CD276, CD147 orchestrates intracellular signaling events that drive cancer cell metabolic adaptation. These interactions contribute to metabolic reprogramming across glucose, lipid, amino acid, and mitochondrial pathways, thereby linking CD147-mediated metabolic plasticity to tumor dissemination and metastasis. By integrating insights into immune and stromal modulation within the tumor microenvironment (TME), this review highlights the multifaceted roles of CD147 and its glycoprotein interactome in shaping the metastatic niche.

Keywords: CD147; CD44; cancer metabolism; pre-metastatic niche formation; tumor microenvironment.

Figure 1

Overview of CD147-mediated metabolic reprogramming within the TME. CD147 modulates glucose, lipid, amino acid, and mitochondrial metabolism through multiple mechanisms across various cancer types. Substantial evidence indicates that CD147 predominantly influences glucose metabolism. PTMs of CD147, including methylation and fucosylation, together with its interaction with MCT1 and MCT4, facilitate lactate export and enhance glucose utilization. Overexpression of CD147 activates the PI3K/AKT/mTOR signaling cascade, leading to increased glucose uptake and elevated lactate production. In addition, CD147 interacts with the long non-coding RNA lnc-CYB561-5, which modulates the expression of glucose metabolism–related genes such as PFK1, G6PI, PCK2, and HK2. CD147 also regulates miR-146a–mediated aerobic glycolysis. Conversely, disruption of the CD147–MCT–carbonic anhydrase IX complex or frameshift mutations in exon 5 of CD147 reduce glycolytic activity and lactate secretion. Through its interactions with various HSPs, CD147 can influence both glucose and mitochondrial metabolism. In lipid metabolism, CD147 activates the AKT/mTOR/SREBP1c and p38 MAPK/PPARα signaling pathways, thereby modulating lipogenesis and fatty acid oxidation. Regarding amino acid metabolism, CD147 reshapes the TME to favor the availability of specific amino acids; CD147 depletion increases the intracellular levels of alanine, proline, glycine, citrate, aconitate, and α-KG, while reducing those of succinate and fumarate.

Figure 2

Overview of CD147-mediated protein interactions, signaling pathways, and functional outcomes. CD147 engages in diverse protein–protein interactions with partners such as CD98, S100A8/A9, EGFR, CD44, and integrins, thereby activating multiple downstream signaling cascades, including AKT, p38, ERK, JNK, and SMAD. The major pathways converge within the MAPK signaling network, wherein p38, ERK, and JNK represent distinct branches. CD147, in complex with EGFR or/and CD44, stimulates the AKT and ERK pathways. Whereas CD147-CD98 complexes predominantly stimulate the AKT pathway, and CD147-S100A8/A9 facilitates the ERK pathway. Interaction with integrins preferentially activates p38, JNK, and SMAD signaling. Through these coordinated signaling events, CD147-associated multiprotein complexes orchestrate metabolic reprogramming, tumor proliferation, EMT, angiogenesis, and immune modulation, collectively fostering a permissive niche for PMN formation.

Figure 3

Overview of diverse therapeutic strategies targeting CD147 structure and signaling. Therapeutic interventions are categorized by their target mechanisms on the CD147 molecule—specifically PTM inhibition, antibody and nanobody targeting, and CAR therapy. PTM Inhibition: Small molecules target specific PTMs; amodiaquine inhibits CD147 phosphorylation, while synthetic compounds, such as 3’-(4-chlorophenyl)-4’,5’-dihydro-[3,5’-biisoxazole]-5-carboxylate, blocking glycosylation reduce MMP production. The flavonoid myricetin promotes CD147 degradation to suppress DNA repair pathways. Antibody and Nanobody Targeting: The glycoengineered antibody Metuzumab binds CD147 via its Fab region and enhances ADCC through a modified Fc region. The humanized single-chain variable fragment HuScFvM6-1B9 specifically targets the Domain 1 epitope, sterically hindering the access of MMPs and MCTs. In contrast, the nanobody Nb 11–1 binds to Domain 2 and can be conjugated with doxorubicin (DOX-11-1) for targeted drug delivery. CAR Therapy: Genetically engineered immune cells express CARs anchored in the cell membrane via transmembrane domains. CD147-CAR-T and CAR-NK cells utilize a CD28 transmembrane domain to trigger cytotoxic degranulation and cytokine secretion. CD147-CAR-Macrophages (CAR-M) incorporate a CD8 transmembrane domain and the FcεRIγ intracellular signaling domain to initiate phagocytosis of CD147-overexpressing tumor cells.