bims-stacyt 2026-05-31 papers

EMBO Rep. 2026 May 27.

Poorly perfused tumor regions harbor T cells with a glucose-dependent effector phenotype.

Marta Riera-Borrull, Víctor Cerdán Porqueras, Sonia Tejedor Vaquero, Claudia Tomaselli González, Mauricio Guzmán, Donata Martinuzzi, Diego Ceacero-Heras, Andrea Cerutti, Jose Aramburu, Cristina López-Rodríguez.

Effector T lymphocytes are avid nutrient consumers, but can function in nutrient-poor tumor microenvironments. Availability of key nutrients such as glucose inside the tumor is not homogeneous, and how tumor-infiltrating T lymphocytes (TILs) differ between regions with better and poorer blood perfusion is not well known. Here we show that in vitro-stimulated TILs can induce substantial production of hallmark glucose-dependent cytokines under glucose concentrations 20 times lower than in blood. In vivo, effector TILs in tumor regions with poor access to blood show comparable capacity for inducing IFNγ and granzyme B to TILs with fuller accessibility; exhibit an enhanced type I IFN response supported by local myeloid cells; and unexpectedly, have reduced expression of immune checkpoint and Treg-associated markers. TILs with poor blood accessibility also have lower biosynthetic activity than highly blood-accessible TILs, yet both compartments depend fundamentally on glucose for ATP production. Thus, effector T lymphocytes in poorly perfused tumor regions can maintain specific glucose-dependent responses, and might be partially protected from inhibitory and exhausting pressure from the tumor microenvironment.

DOI: https://doi.org/10.1038/s44319-026-00799-0

Int J Mol Sci. 2026 May 21. pii: 4619. [Epub ahead of print]27(10):

Lactate Uptake by MCT4 Facilitates Stability and Suppressive Function of Tumor-Infiltrating Regulatory T Cells by Promoting Foxp3 Lactylation.

Zhaofei Wu, Yuwei Liu, Wei Xian, Jingyi Wang, Ziheng Zhao, Chunliang Qi, Yu Zhang, Wei Wang.

High lactate concentration is a hallmark of the tumor microenvironment (TME). Regulatory T cells (Tregs) exhibit unique metabolic adaptability to this lactate-rich environment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that the monocarboxylate transporter MCT4 is upregulated in tumor-infiltrating Tregs and mediates direct lactate uptake. Using Treg-specific conditional knockout (cKO) mice, we show that MCT4 deficiency does not affect basal Treg development but abrogates lactate-induced Foxp3 stabilization and impairs Treg suppressive function. Mechanistically, MCT4-mediated lactate uptake promotes the lactylation of Foxp3 at lysine 277 (K277), which competitively inhibits its ubiquitination, thereby enhancing Foxp3 protein stability and nuclear localization. Nuclear Foxp3 subsequently interacts with IRF3 to promote IL-10 transcription and secretion. In the B16 melanoma model, MCT4-deficient Tregs display compromised stability and reduced tumor infiltration, leading to enhanced CD8+ T cell effector function and attenuated tumor growth. Collectively, our findings reveal that MCT4-mediated lactate uptake sustains Treg stability and function through Foxp3 lactylation, identifying MCT4 as a potential therapeutic target for modulating Treg activity in cancer.

Keywords: MCT4; lactate; lactylation; treg; tumor immunity

DOI: https://doi.org/10.3390/ijms27104619

J Immunother Cancer. 2026 May 28. pii: e015038. [Epub ahead of print]14(5):

ATF4 promotes immune evasion in oral squamous cell carcinoma by suppressing autophagic PD-L1 degradation.

Kui-Ming Wang, Lin-Zhou Zhang, Jia-Jie Liang, Zao Wang, Xiao-Le Wang, Jie Zhang, Gang Chen, Wei Zhang.

BACKGROUND: Immune checkpoint blockade targeting programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) has revolutionized cancer therapy. However, its efficacy is frequently limited by primary and acquired resistance. While inflammatory signals transiently upregulate PD-L1 transcription, post-translational regulation is crucial for its sustained expression in chronically stressed tumors. Whether and how tumor-intrinsic stress-response pathways control PD-L1 stability to promote immune evasion remains incompletely understood.
METHODS: Using human oral squamous cell carcinoma (OSCC) specimens, syngeneic mouse models, single-cell RNA sequencing, and genetic and pharmacological perturbations, we dissected the role of the unfolded protein response effector ATF4 in regulating PD-L1 stability and antitumor immunity. Its therapeutic potential was further evaluated in immunocompetent mice treated with anti-PD-1 therapy.
RESULTS: We identified ATF4 as a tumor-intrinsic driver of immune evasion. In malignant cells, ATF4 induced reactive oxygen species (ROS), which activated the AKT-mTOR pathway and suppressed autophagy, thereby stabilizing the PD-L1 protein independently of inflammatory cues. Genetic ablation of ATF4 or pharmacological inhibition of ROS-AKT-mTOR signaling restored autophagic flux, reduced PD-L1 levels, and enhanced CD8+ T-cell infiltration and function. When combined with PD-1 blockade, ATF4 targeting further suppressed tumor growth. Clinically, ATF4 expression was inversely correlated with CD8+ T-cell infiltration and autophagy markers, positively correlated with PD-L1 levels, and predicted a poor response to immunotherapy in patients with OSCC.
CONCLUSIONS: Our findings establish ATF4 as a stress-responsive regulator of PD-L1 proteostasis, directly linking tumor-intrinsic stress adaptation to immune checkpoint stabilization and therapy resistance. Targeting the ATF4-ROS-AKT-mTOR axis may represent a promising strategy to overcome resistance to PD-1/PD-L1 blockade.

Keywords: Head and Neck Cancer; Immune Checkpoint Inhibitor; Immunotherapy; Tumor microenvironment - TME

DOI: https://doi.org/10.1136/jitc-2026-015038

Front Oncol. 2026 ;16 1715589

Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.

Ryotaro Tomida, Keisuke Ozaki, Yukako Tanaka, Rina Komatsu, Syuya Hirata, Takayuki Uchida, Junya Furukawa, Takeshi Nikawa, Tomoya Fukawa.

Background: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and impaired response to conventional nutritional support, affecting up to 80% of advanced cancer patients and contributing to poor prognosis. Excessive fatty acid oxidation and mitochondrial reactive oxygen species (ROS) generation have been implicated in cachexia-associated muscle atrophy, but the underlying mechanisms remain unclear.
Methods and results: We investigated the role of cancer cell-derived exosomes in metabolic alterations of skeletal muscle cells. Exosomes from a pro-cachectic renal carcinoma cell line (RXF393) induced myotube atrophy, enhanced mitochondrial ROS production, impaired mitochondrial respiration, and reduced expression of isocitrate dehydrogenase 2 (IDH2) and respiratory chain complex subunits compared to observations in non-cachectic controls. miRNA profiling identified enrichment of miR-1260b in pro-cachectic exosomes, and transfection with a miR-1260b mimic reproduced these phenotypes, including IDH2 downregulation, impaired antioxidant defense, and mitochondrial dysfunction.
Conclusion: These findings demonstrate that cancer-derived exosomal miR-1260b suppresses IDH2, disrupts mitochondrial redox balance, and promotes muscle wasting. This study reveals a mechanistic link between exosomal miRNAs and mitochondrial dysfunction in cancer cachexia and suggests that maintaining mitochondrial redox homeostasis may represent a novel therapeutic strategy.

Keywords: cancer cachexia; exosome; isocitrate dehydrogenase 2; miR-1260b; mitochondrial dysfunction; reactive oxygen species; renal cell carcinoma

DOI: https://doi.org/10.3389/fonc.2026.1715589