Enhancing Immunotherapy in Diffuse Large B-Cell Lymphoma: The Synergistic Potential of Metabolic Checkpoint Inhibitors and Immunomodulation.

For many patients with diffuse large B-cell lymphoma (DLBCL), frontline chemoimmunotherapy is curative; nonetheless, up to 40% of patients develop relapse or refractory disease. Immunotherapeutic approaches, such as immunomodulatory drugs, bispecific antibodies and chimeric antigen receptor T-cell therapy, have improved outcomes for relapsed/refractory DLBCL over the past ten years. However, treatment failure is still frequent because of tumor antigen loss, T-cell dysfunction, and an immunosuppressive tumor microenvironment (TME). DLBCL is a highly metabolically active cancer that impairs efficient anti-tumor immune responses by depleting vital nutrients and producing immunosuppressive metabolites such lactate, adenosine, and kynurenine. Targeting metabolic checkpoints, such as glutamine metabolism, indoleamine 2,3-dioxygenase, adenosine signaling, and lactate transport, may remodel the TME and improve the effectiveness of immunotherapy, according to new research. The immune metabolic interaction that restricts long-lasting responses is the main topic of this study, which summarizes current immunotherapeutic strategies in DLBCL. To improve T-cell fitness and overcome immunotherapy resistance, we critically assessed the preclinical and early clinical data supporting metabolic checkpoint inhibition. We also emphasize translational issues and potential future paths for logical combination treatments. Importantly, this review distinguishes itself from existing literature by specifically focusing on the integration of metabolic checkpoint inhibition with established immunotherapies in DLBCL, an area that remains underexplored. While preclinical data are promising, clinical evidence for many metabolic checkpoint inhibitors in DLBCL remains limited, and further prospective clinical studies are required to validate their therapeutic potential.