Metabolic reprogramming as the next frontier in cell therapy and cancer immunotherapy for solid tumors

Cell-based immunotherapies offer a promising alternative for treating certain hematological malignancies. The therapeutic landscape has expanded to include chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor (TCR)-T cells, CAR natural killer (CAR-NK) cells, invariant NKT cells, macrophage-based therapies, dendritic cell vaccines, and induced pluripotent stem cell (iPSC)-derived immune cells. Although not all of these therapies have received clinical approval, cancer treatment research continues to advance, including armored CAR-T cells, logic-gated CARs, gene-edited allogeneic products, in vivo CAR engineering, and combination strategies that integrate checkpoint inhibition with adoptive cellular therapy.Despite the above-mentioned advances, the clinical success observed in hematological malignancies has not been extended to most solid tumors, particularly in lung and breast cancers. When engineered immune cells are transferred, they encounter multiple challenges within the tumor microenvironment (TME). Importantly, metabolic reprogramming may be a key contributor to these therapeutic failures, as tumor cells compete aggressively with immune cells for nutrients such as glucose, glutamine, arginine, and lipids, while simultaneously producing immunosuppressive metabolites such as lactic acid, kynurenine, adenosine, and reactive oxygen species (ROS). Moreover, the TME is highly heterogeneous and contains zones with varying degrees of hypoxia, acidic pH, and/or limited nutrients, which collectively impair T-cell persistence, CAR-T cell expansion, NK-cell cytotoxicity, and antigen-presenting cell function.This Research Topic aims to characterize the challenges and reveal potential solutions for the next generation of cellular immunotherapies against solid cancers. These challenges may include physical stromal barriers, immunosuppressive myeloid populations, T-cell exhaustion, severe metabolic stress, tissue disorganization, and the extent of tumor metabolic reprogramming. Both tumor cell and immune metabolism have become key determinants of the safety and efficacy of immune-cell therapies, underscoring the need to integrate discoveries from cancer metabolism, immunology, bioengineering, and translational medicine to develop metabolically resilient cellular therapies capable of overcoming the hostile TME of solid tumors.This Research Topic particularly welcomes studies addressing the major obstacles limiting cellular immunotherapy in solid tumors, including:Nutrient competition between tumor cells and therapeutic immune cells.Lactate accumulation, extracellular acidosis, and hypoxia-induced immune dysfunction.Mitochondrial exhaustion and metabolic insufficiency of CAR-T and NK cells.Limited trafficking and infiltration across stromal barriers in cancer.Biomarkers predicting metabolic fitness and response to adoptive cell therapy.Antigen heterogeneity and adaptive immune escape.Immunosuppressive myeloid cells, regulatory T cells, and cancer-associated fibroblasts.Metabolic mechanisms underlying T-cell exhaustion.Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal.Topic Coordinator Dr. Rajkumar Arumugam Rajasekaran is employed as a Senior Scientist at Bristol Myers Squibb. Topic editors: Aida Susana Romero-Garcia, Heriberto Prado-Garcia Source: https://www.frontiersin.org/research-topics/85152/metabolic-reprogramming-as-the-next-frontier-in-cell-therapy-and-cancer-immunotherapy-for-solid-tumors