CAR-T cells, which are genetically programmed to specifically recognise and kill target cells, have altered the therapeutic landscape of lymphoma.

After the tumour antigens are identified by scFv, CAR-T cells execute anti-tumour activity through granzyme and perforin secretion, inducing cell apoptosis in a Fas-FasL-dependent pathway and producing inflammatory cytokines to antagonise the immunosuppressive tumour microenvironments (TME) and induce host immune responses.

However, CAR-T cell therapy still faces many challenges owing to the heterogeneity of tumour cells, interference from TME, T cell exhaustion, as well as severe adverse events.

Recent years, advances in tumour immunology and genetic engineering have driven CAR evolution.

These new generations of CARs armed with diverse molecular weapons have made significant progress in enhancing the accuracy of recognition, stimulating endogenous immune responses, strengthening killing activity, resisting TME and exhaustion, and improving safety and flexibility, thus gradually overcoming the limitations of CAR-T cell therapy.

This review focuses on the advancements of CAR-T cells in the treatment of lymphoma, summarises the newly emerged modification strategies of CAR, and elucidates their potential prospects.

A team of researchers from the Department of Haematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, published in Cancer Biology & Medicine.

This paper analyses the mechanisms of various CAR-T modification strategies in counteracting tumour immune escape and TME, while detailing the structures and functions of novel CAR-T designs.

Multi-target CAR-T combats antigen loss, TRUCKs enhance cytotoxic activity and stimulate host immune responses through cytokine delivery, and immune checkpoint-switching receptor converts inhibitory signals into immune-activating stimuli to overcome TME-induced exhaustion.

Beyond clinically established CAR-T therapies, the review also emphasises the roles of universal CAR-T (including iPSC-derived, autologous, and in vivo-generated CAR-T), epigenetics, and metabolism.

Notably, glycolysis, oxidative phosphorylation, histone acetylation, and DNA methylation interact in a tightly regulated network to influence CAR-T cell phenotype and exhaustion, ultimately shaping systemic antitumor immunity.

Collectively, superior CAR-T cells are expected to have accurate identification, strong killing ability, stability and persistence, high security and flexibility, and easier accessibility.

More sophisticated modifications mean greater operational difficulties and higher genetic risks.

There may be contradictions among a variety of strategies, and we need to find a balance between the efficacy and memory, lethality and safety.

Source: Tsinghua University Press