Adipose Tissue-Associated Lipid Serum Signatures Modulate Efficacy and Toxicity of CAR-T Cell Therapy in Lymphoid Malignancies

Abstract The host metabolic state is a key regulator of immune cell function and may influence outcomes of T-cell–based therapies. To investigate the role of adiposity in CAR-T cell therapy, we integrated computed tomography–based body composition analysis with targeted mass spectrometry of 158 longitudinal serum samples from 54 patients with relapsed B-cell lymphoma. We identify distinct adipose tissue–associated lipid classes linked to survival and the development of cytokine release syndrome (CRS), with visceral adiposity–dependent dynamics during therapy. Among these, associations between acylcarnitines and phosphatidylethanolamines with CRS were independently validated in a separate cohort of 17 patients with B-cell lymphoma and myeloma. In parallel, single-cell RNA sequencing of murine bone marrow immune cells in vitro cultured under obesity-mimicking conditions revealed a pro-inflammatory transcriptional program in key immune cell subsets, implicating adipose-derived metabolic signals in immune modulation. These findings highlight a link between host metabolic and body compositional states and CAR-T function and support the integration of metabolic profiling into precision immunotherapy.