Disruption of translational and mitochondrial homeostasis is identified as a central mechanism limiting NK-cell persistence in solid tumours and provides a framework for restoring effective innate anti-tumour responses.
Abstract
Natural killer (NK) cells infiltrate many solid tumours, yet the mechanisms that determine their functional heterogeneity across tumour types remain poorly understood. Differences in tumour immunogenicity, inhibitory signalling, and nutrient availability have all been implicated, but unifying explanations are lacking. Here, we compared four syngeneic tumour models implanted at identical anatomical sites to isolate tumour-intrinsic effects on NK-cell fate. Tumour-infiltrating NK cells displayed striking tumour-specific differences in cytokine production, cytotoxic protein expression, and persistence. These differences were not explained by cytokine availability or global features of the tumour metabolic environment. Instead, quantitative proteomics and time-resolved in vivo labelling revealed that NK cells enter tumours in a functionally competent state but rapidly diverge thereafter. In suppressive tumour microenvironments, NK cells undergo early mitochondrial loss, translational repression, and impaired proteostatic responses, accompanied by increased apoptotic priming. These defects result in reduced effector function and failure of intratumoural persistence despite preserved recruitment. In contrast, permissive tumours sustain NK-cell translational capacity, cytokine responsiveness, and long-term residency. Together, these findings identify disruption of translational and mitochondrial homeostasis as a central mechanism limiting NK-cell persistence in solid tumours. This work establishes early tumour-induced defects in protein synthesis and cellular fitness as key constraints on durable NK-cell immunity and provides a framework for restoring effective innate anti-tumour responses.
Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide. Treatment failure is driven in large part by a profoundly immunosuppressive tumour microenvironment (TME) in which metabolic competition between GBM cells, bone marrow-derived immunosuppressive myeloid cells, and cytotoxic T lymphocytes determines cellular dominance. This review frames the GBM TME through the lens of metabolic cell competition: a process by which differential metabolic fitness, mediated principally through glucose and glutamine consumption, establishes a suppressive hierarchy that forecloses effective anti-tumour immunity. Aerobic glycolysis in GBM cells produces lactate, which polarises tumour-associated macrophages toward immunosuppressive phenotypes via GPR81/HIF-1alpha signalling and directly impairs T cell effector function through extracellular acidification and competition for monocarboxylate transporter capacity. GBM cells and immunosuppressive myeloid cells cannot sustain their proliferative and immunosuppressive programmes without glucose and glutamine; cytotoxic memory T cells, whose effector functions are energetically but not biosynthetically demanding, retain the capacity to function through fatty acid oxidation when these substrates are restricted. Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit. Pharmacological ketosis elevates beta-hydroxybutyrate, an endogenous HDAC inhibitor that further augments T cell effector function through NLRP3 inflammasome suppression. The mechanistic and clinical evidence for each intervention is reviewed, metabolic engineering strategies for increasing T cell competitive fitness are described, and principal research gaps are identified. GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent competitive coalition whose simultaneous disruption is the central therapeutic proposition reviewed. Evidence is synthesised from in vitro metabolic competition experiments, immune-competent murine GBM models, mechanistic pharmacology studies, and early-phase clinical pharmacodynamic data in human GBM.
A complementary therapeutic strategy is discussed: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity.
L. Saltis, Liew Jun Mun· Pathology, Research and Prac...· 0 citations
Multiple clinical and translational studies have shown that infiltration of tumour-associated neutrophils is associated with advanced disease stages, increased metastatic spread, therapeutic resistance, and poorer overall survival across various cancer types. Beyond their traditional role as first responders to tissue damage and pathogen infection, neutrophils within the tumour microenvironment (TME) display remarkable functional plasticity, adopting phenotypes that can promote angiogenesis, extracellular matrix remodelling, immune suppression, and tumour cell invasion. Importantly, it is now recognised that the prognostic impact of neutrophils is highly context-dependent, shaped by tumour type, stage, and the evolving inflammatory milieu. Intravital imaging studies have revealed dynamic neutrophil behaviours, including distinct migratory patterns between intra-tumoural and peri-tumoural regions, interactions with tumour and immune cells, and contributions to processes such as metastasis and immune suppression. However, there is a lack of understanding of how transcriptionally defined neutrophil subsets translate into specific functional and behavioural states in the TME in vivo. This mini-review spotlights intravital imaging approaches that illuminate neutrophil dynamics in tumours. We also discuss how extrinsic regulators, including cancer-associated fibroblasts and neural inputs, direct neutrophil dynamics, further contributing to TME complexity.
A G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy is uncovered, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity.
Cenk Celik, William A. Weston, Thais de Moraes-Lacerda et al.· Genome Medicine· 1 citation
The tumour microenvironment imposes severe metabolic constraints that reshape anti-tumour immunity across the cancer-immunity cycle. Rather than serving merely as passive byproducts of tumour growth, tumour-derived metabolites and nutrient imbalances act as potent metabolic checkpoints-stage-specific barriers that disrupt the functional progression of dendritic cells (DCs) and T cells from antigen presentation to effective tumour clearance. In this review, we propose a framework that overlays the cancer-immunity cycle with major metabolic checkpoints, including glucose and amino acid competition, acidosis and lipid overload, to clarify how distinct metabolic stresses create immune bottlenecks at different stages of the anti-tumour response. We then discuss how distinct tumour metabolic phenotypes, characterized by high glycolysis, amino acid dependency or lipid dysregulation, generate local environmental stresses that differentially reprogram DC function and T cell fitness. Particular emphasis is placed on the DC-T cell axis as a critical site where multiple metabolic defects converge, destabilizing antigen presentation, co-stimulation and immunological synapse function. We further survey emerging therapeutic strategies aimed at restoring the DC-T cell axis and effective anti-tumour immunity, ranging from small-molecule metabolic inhibitors to metabolically engineered adoptive cell therapies designed to function in hostile microenvironments. Finally, we highlight emerging technologies such as single-cell and spatial multi-omics, real-time metabolic imaging and microphysiological systems that can resolve the spatiotemporal heterogeneity of tumour immunometabolism and support more precise immunometabolic interventions.
Minkyu Cho, Minkyung Song· Experimental and Molecular M...· 0 citations