Optimization of CAR-T therapy based on metabolic remodeling of the tumor immune microenvironment in diffuse large B-cell lymphoma.

Abstract

Diffuse large B-cell lymphoma (DLBCL), a common subtype of non-Hodgkin's lymphoma, faces the severe challenge of relapsed/refractory cases, with limited efficacy of existing therapies such as the R-CHOP regimen and second-line treatment plans. There is an urgent need for innovative treatment strategies. CAR-T therapy has shown revolutionary potential in the treatment of DLBCL, but its efficacy is limited by immune suppression and metabolic competition mediated by the tumor microenvironment (TME). Immunosuppressive cells and cytokines in the TME lead to the exhaustion of CAR-T cell functions, while metabolic competition puts CAR-T cells at a disadvantage in the uptake of key metabolites, limiting their proliferation and effector functions. Metabolic reprogramming, as a core mechanism of TME regulation, connects the functions of tumor cells and immune cells and is a key hub for enhancing the efficacy of CAR-T therapy. Among them, low glucose levels in the TME can activate the glycolytic pathway of CAR-T cells, but also lead to mitochondrial dysfunction and reduced cytotoxicity. Targeting the metabolic remodeling of the TME, in combination with metabolic regulatory drugs and CAR-T synergy strategies, as well as the development and translation of drugs, is expected to significantly enhance the efficacy of CAR-T therapy in the treatment of DLBCL, bringing new hope to patients. Future research should further explore the specific mechanisms of metabolic reprogramming, optimize the design and application of metabolic regulatory drugs, and accelerate the clinical translation of drugs to achieve the maximum potential of CAR-T therapy in the treatment of DLBCL.