Since the FDA’s landmark approval of the first CAR-T cell therapy in 2017, tumor immunotherapy has transformed dramatically. To date, at least six CAR-T therapies have been approved, heralding a new era in targeted treatments. Recently, clinical data revealed the promising efficacy of Anti-CD19 CAR-T in treating refractory systemic lupus erythematosus, marking a significant expansion of CAR-T applications beyond malignancies. This Research Topic in Frontiers in Immunology provides a comprehensive update on the rapidly evolving CAR-T landscape, covering advancements in technology, targeting strategies, and underlying mechanisms.

While CAR-T therapies have shown remarkable efficacy in hematologic cancers, significant challenges remain. Issues such as antigen escape, relapse, cytokine release syndrome (CRS), on-target tumor toxicity, and neurotoxicity have posed barriers to broader success. Emerging solutions, including dual-target CARs, SynNotch CARs, and iCARs, are addressing these issues. CAR-T efficacy in solid tumors remains limited, with obstacles such as tumor heterogeneity, an immunosuppressive microenvironment, and T cell exhaustion. Novel approaches, such as multi-target CARs, chemokine receptor-expressing CARs, and antibody-secreting CARs, are under investigation to overcome these barriers.

In the realm of autoimmune diseases, advancements like anti-DSG3 CAR and anti-Musk CAR have shown clinical promise, particularly in anti-CD19 CAR research. This growing body of work signals potential new directions for CAR-T applications. Parallel research on other immunotherapies and new target discovery is also advancing rapidly, with efforts underway to refine CAR construct delivery through non-viral and site-specific genome insertion methods.

This Research Topic aims to explore the wide-ranging potential of CAR-T cell therapies for both cancer and non-cancer indications. Key objectives include deepening our understanding of CAR-T cell mechanisms, enhancing efficacy and safety, and expanding CAR-T applications to autoimmune and other non-cancerous diseases. Critical questions include strategies to address antigen escape and tumor heterogeneity, mitigate on-target off-tumor toxicity, and improve CAR-T cell persistence and efficacy in vivo. Novel CAR targets and delivery techniques will also be highlighted.

To further the field, we welcome contributions on themes such as:
•Enhancing in vivo persistence and efficacy of CAR-T cells
•Reducing on-target off-tumor toxicity
•Addressing tumor heterogeneity and immunosuppressive microenvironments
•Advancements in in vitro and in vivo CAR construct delivery
•Exploring novel targets for non-cancer indications

We encourage submissions of Original Research and Review articles focusing on clinical data, unmet medical needs, and innovative mechanisms in CAR-T therapies. Your contributions will play a crucial role in advancing this dynamic field, opening new avenues for impactful therapeutic applications.

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Frontiers in Immunology

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