Overcoming CAR-T bottlenecks in high-risk DLBCL: a molecular subtyping enhancement strategy

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and exhibits significant molecular heterogeneity, leading to varied treatment responses among patients. Although Chimeric Antigen Receptor T-cell therapy (CAR-T) has made remarkable progress in relapsed/refractory (R/R) DLBCL, particularly in patients resistant to standard treatments, the therapeutic efficacy of CAR-T therapy remains inconsistent for high-risk subtypes, such as double-hit/triple-hit lymphoma (DHL/THL) and TP53 mutations. This paper focuses on the molecular subtyping of DLBCL and its application in CAR-T therapy. By analyzing factors such as metabolic stress, immune evasion, and epigenetic regulation, this study reveals how these mechanisms influence the function and efficacy of CAR-T cells. Furthermore, it discusses strategies for overcoming treatment challenges in high-risk subtypes through molecular profiling, metabolic modulation, epigenetic interventions, and multi-target combination therapies. The paper also explores future research directions in CAR-T cell engineering and immune evasion mechanisms. This research provides a novel theoretical framework for personalized treatment and offers valuable insights for clinical treatment strategies for high-risk DLBCL patients.