Metabolic Interactions in the Tumor Microenvironment of Classical Hodgkin Lymphoma: Implications for Targeted Therapy

Abstract

Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed-Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies-such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies-which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL.

Keywords: Hodgkin lymphoma; cell metabolism; therapeutic strategies; tumor microenvironment.

Figure 1

Potential therapeutic targets and agents modulating glucose, fatty acid, and amino acid metabolism in classical Hodgkin lymphoma (cHL). LAT1—L-type amino acid transporter 1, MCT 1 and 4—monocarboxylate transporter 1 and 4, 2-DG—2-deoxy-D-glucose, GLUT1 and 3—glucose transporter 1 and 3, CPT1 and 2—carnitine palmitoyltransferase 1 and 2, UDP-GlcNAc—uridine diphosphate N-acetylglucosamine, ATP—adenosine-5′-triphosphate, ADP—adenosine-5′-diphosphate, Na⁺—sodium ion, and K⁺—potassium ion.

Figure 2

Selected immunotherapeutic targets and cellular interactions in cHL. LAG-3—Lymphocyte activation gene-3; CD73—ecto-5′-nucleotidase; CD39—ectonucleoside triphosphate diphosphohydrolase-1; TIGIT—T-cell immunoreceptor with Ig and ITIM domains; CD155—poliovirus receptor (PVR), a ligand for TIGIT; CTLA-4—cytotoxic T-lymphocyte antigen-4; CCL22—chemokine (C-C motif) ligand 22; CCL17—chemokine (C-C motif) ligand 17; CCR4 C—C chemokine receptor type 4; MGD024—a bispecific antibody targeting CD123 and CD3; CPI—checkpoint inhibitor; PD-1—programmed cell death protein 1; PD-L1—programmed death-ligand 1, a ligand for PD-1; CSF1R—colony-stimulating factor 1 receptor; SIRPα—signal regulatory protein alpha; AFM13—bispecific antibody construct targeting CD30 and CD16A; and CD47—a transmembrane protein that interacts with SIRPα.