Combating Tumor Resistance and Exhaustion in Lymphoma

CAR-T cells are genetically engineered to identify and destroy specific target cells. They have significantly changed how lymphoma is treated.

Once CAR-T cells recognize tumor antigens through scFv, they perform anti-tumor functions. These include releasing granzyme and perforin to trigger apoptosis via a Fas-FasL-dependent pathway. They also release inflammatory cytokines to reduce the effects of the immunosuppressive tumor microenvironment (TME) and activate the host immune system.

Despite their promise, CAR-T cell therapy still faces several challenges. These include tumor cell diversity, TME influence, T cell exhaustion, and the risk of serious side effects. Recent advances in tumor immunology and genetic engineering have contributed to the development of more advanced CARs.

Next-generation CARs incorporate a range of molecular tools. These tools improve target recognition, strengthen immune responses, increase cytotoxicity, reduce TME effects and exhaustion, and enhance safety and adaptability. These developments are helping to overcome limitations in current CAR-T therapies.

The study focuses on recent progress in CAR-T cells for treating lymphoma. It reviews new CAR modification strategies and explores potential future uses.

A research team from the Department of Hematology at the Second Affiliated Hospital, Zhejiang University School of Medicine, published the study in Cancer Biology & Medicine. The study looks at how different CAR-T modifications work to counter tumor immune evasion and TME. It also explains the design and function of new CAR-T structures.

Multi-target CAR-T addresses the problem of antigen loss. TRUCKs (T cells redirected for universal cytokine killing) enhance cytotoxicity and stimulate immune responses by delivering cytokines. Immune checkpoint-switching receptors help reduce TME-induced exhaustion by converting inhibitory signals into activating ones.

Beyond current CAR-T therapies, the study also discusses the importance of universal CAR-T approaches. These include iPSC-derived, autologous, and in vivo-generated CAR-T cells. It also explores the roles of epigenetics and metabolism.

Processes such as glycolysis, oxidative phosphorylation, histone acetylation, and DNA methylation interact in a tightly regulated network. This network influences CAR-T cell characteristics and exhaustion, shaping the overall antitumor response.

In conclusion, improved CAR-T cells are expected to offer accurate targeting, strong killing ability, long-term stability, high safety, adaptability, and broader accessibility.

However, adding more complex modifications can make production more difficult and increase genetic risks. Different strategies may also conflict, requiring a careful balance between treatment strength and safety, as well as between effectiveness and long-term immune memory.