Immunobiology of chimeric antigen receptor-T (CAR-T) cells in cancer immunity

Chimeric antigen receptor-T (CAR-T) cell therapy represents a major breakthrough in cancer immunotherapy, providing remarkable clinical benefits for various hematologic malignancies. However, the translation of these successes to wider patient populations and solid tumors remains challenging due to intricate immunobiological obstacles. Factors such as inadequate CAR-T cell trafficking, short-lived persistence, tumor antigen diversity and immune escape, as well as T cell exhaustion and metabolic limitations all contribute to variable efficacy. Furthermore, the highly suppressive tumor microenvironment (TME) and immune-related toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), underscore our incomplete understanding of CAR-T cell interactions with both tumor and host immunity. Recent evidence highlights how CAR design, patient-specific immune context, and real-time functional states of T cells collectively determine therapeutic outcomes, yet significant knowledge gaps and active debates persist regarding the mechanisms underlying resistance, relapse, and immunotoxicity. To date, CAR-T therapies are approved and available on the market for only a limited set of malignancies, such as multiple myeloma, acute lymphoblastic leukemia, and lymphoma. An expansion of therapeutic prospects for CAR-T therapy to patients with other malignancies would require robust translational science.This Research Topic aims to elucidate the cancer-relevant immunobiology that underpins CAR-T cell function, persistence, and safety. By assembling mechanistic studies, clinical investigations, and translational research, we seek to clarify how various CAR designs, manufacturing protocols, and features of the tumor microenvironment interact to shape CAR-T cell activity and determine treatment success or failure. Particular focus will be placed on the molecular and cellular mechanisms governing antitumor responses and resistance pathways, as well as the integrative use of biomarkers for optimizing next-generation CAR engineering and rational combination therapies. Furthermore, we seek to identify the role of CAR-T therapies in malignancies for which these therapies are not currently commercially available. Examples include, but are not limited to, acute myeloid leukemia, breast cancer, lung cancer, and colon cancer.This Research Topic will encompass studies that dissect the diversity and limitations of CAR-T cell biology in cancer immunity and immunotherapy. Articles are invited that address, but are not limited to, the following themes:• Mechanisms of CAR-T efficacy, persistence, and failure in both hematologic and solid malignancies• Pathways of tumor immune escape, including antigen loss, heterogeneity, and immune editing• Differentiation states, exhaustion, memory formation, and apoptosis within CAR-T populations• CAR-T cell trafficking and infiltration within solid tumors, and the barriers posed by stroma and vasculature• Immunosuppressive properties of the tumor microenvironment, including roles of myeloid cells, Tregs, hypoxia, and immunometabolites• Immune checkpoint pathways and their influence on CAR-T cell activity and dysfunction• Metabolic challenges in the TME and their effects on CAR-T cell fitness and expansion• Crosstalk between CAR-T cells and innate immune compartments, and mechanisms underlying inflammatory toxicities• Innovations in CAR design and engineering for improved specificity, safety, and efficacy• Integration of systems immunology, single-cell, and multi-omics approaches for CAR-T monitoring and biomarker discovery• Translational model development, including organoids and humanized mouse platforms, to recapitulate tumor-immune interactions• Prospects on clinical translation of novel CARs in solid tumor biology• Disease models or CAR-T engineering that allows for widening the currently narrow therapeutic window for CAR-T therapies such that toxicities can be minimizedBy fostering a comprehensive exploration of these topics, this Research Topic will advance our integrated understanding of CAR-T cells as living drugs within complex cancer ecosystems, ultimately accelerating the development of safer, more powerful, and more widely applicable cellular therapies.Topic Editor Dr. Saurabh Dahiya is on the advisory board/consulting for the following: Kite Pharmaceuticals/Gilead Pharma, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Novartis Pharmaceuticals, Johnson and Johnson (Jansen Pharmaceuticals). All other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Shyam Patel, Saurabh Dahiya Source: https://www.frontiersin.org/research-topics/80170/immunobiology-of-chimeric-antigen-receptor-t-car-t-cells-in-cancer-immunity