Lymphomas, predominantly of B cell origin, vary in their aggressiveness and response to chemotherapy. Despite the success of second-generation anti-CD19 chimeric antigen receptor T cells (anti-CD19-CAR2-T) in treating some B cell malignancies, their effectiveness against aggressive B cell lymphomas (BCL) has been limited. Researchers have now developed a fourth-generation CAR-T cell (CAR4-T cells) that includes three costimulatory domains, showing high cytotoxic activity against various tumor models. However, the PD-1/PD-L1 interaction, which plays a crucial role in T cell suppression, remains a significant barrier to CAR-T cell therapy effectiveness. To overcome this, the researchers engineered anti-CD19-CAR4-T cells to secrete anti-PD-L1 single-chain variable fragment (scFv), creating anti-CD19-CAR5-T cells. These cells showed superior cytotoxic functions, cytokine secretion levels, and proliferation compared to anti-CD19-CAR4-T cells. Furthermore, they showed effective cytotoxicity against cancer cells expressing both CD19 and PD-L1, even at low effector-to-target ratios. This approach could potentially reduce treatment-related toxicity and costs. However, further in vivo studies and clinical trials are needed to confirm the safety and efficacy of anti-CD19-CAR5-T cells for treating aggressive BCL.