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Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity
Dominik Soll. et al.
Nature Immunology. 2024
This study reveals the significant impact of high NaCl concentrations in the tumor microenvironment on cellular metabolism and immune function, specifically enhancing the effector functions of human CD8+ T cells through a Na⁺/K⁺-ATPase-dependent mechanism, which translates extracellular NaCl levels into amplified TCR signaling and metabolic activation. High NaCl increases Na⁺/K⁺-ATPase activity, leading to membrane hyperpolarization and enhanced Ca²⁺ influx via ORAI channels, which strengthens proximal TCR signaling and upregulates mTOR and SGK1 pathways. This metabolic rewiring promotes glycolysis and Glut-1 expression in CD8+ T cells, boosting their cytotoxicity. At the same time, NaCl inhibits mitochondrial respiration in regulatory T cells (Tregs), reducing their suppressive capacity. These distinct effects on T cell subsets reflect their intrinsic metabolic differences, with CD8+ T cells relying on glycolysis and Tregs on lipid oxidation. In vivo, CD8+ T cells preconditioned with high NaCl suppressed tumor growth in pancreatic cancer models, and CAR-T cells demonstrated enhanced antigen-specific cytotoxicity. While these findings suggest a promising therapeutic strategy to enhance T cell-mediated tumor control, the risk of T cell exhaustion under prolonged high NaCl conditions necessitates further clinical investigation to balance short- and long-term outcomes. This research offers a novel perspective on NaCl as a key modulator of T cell activity and its potential application in cancer immunotherapy.
DOI: 10.1038/s41590-024-01918-6
02
Kevin M Tharp. et al.
Nature Cancer. 2024
This study demonstrates that the stiff, fibrotic tumor microenvironment (TME) plays a dual role in suppressing antitumor immunity, functioning not only as a physical barrier but also as a driver of metabolic reprogramming. The synergy between TGFβ signaling and the fibrotic stroma induces a collagen ECM-synthetic phenotype in tumor-associated macrophages (TAMs), which produce collagens like collagen VI and XII, contributing to fibrosis. Beyond fibrosis, TAMs metabolically reprogram the TME by enriching it with ornithine, a metabolite that suppresses CD8+ cytotoxic T lymphocyte (CTL) proliferation and activation, ultimately impairing antitumor immunity and reducing responsiveness to immune checkpoint blockade (ICB). Contrary to the traditional view that fibrosis primarily hinders T cell infiltration, this study highlights the critical role of TAM-driven metabolic changes in creating an immunosuppressive environment. The TME’s physical properties mimic wound-healing processes, triggering TAM phenotypes adapted for tissue repair but maladaptive in tumors, as these phenotypes alter arginine metabolism to suppress T cell activity. Therapeutic strategies targeting the metabolic imbalance in the TME, such as localized arginine synthesis using Arg-ECN to restore the arginine–ornithine ratio, show promise in enhancing CTL function and improving ICB efficacy. These findings underscore the importance of addressing both mechanical and metabolic factors in the TME to restore effective antitumor immunity.
DOI: 10.1038/s43018-024-00775-4
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