bims-spamet 2026-04-19 papers

bims-spamet

Biomed News

on Spatial metabolomics of T cells

Issue of 2026–04–19
24 papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven

Stem-like PD-1+TCF-1+ CD8+ T cells result from helpless priming and rely on CD4+ T-cell help to complete their cytotoxic effector differentiation.
The construction of CD8+ T cell-associated molecular subtypes in esophageal squamous cell carcinoma reveals tumor heterogeneity, tumor microenvironment, and immunotherapy.
Targeting the amino acid metabolic axis: the Achilles' heel of tumor cells.
Molecularly imprinted polymer-based electrochemical sensor for L-tyrosine competition-mediated T cell exhaustion.
Endometrial immune dysregulation shapes CD8+ T cell mediated reproductive outcomes in recurrent implantation failure: an integrated mechanistic and predictive analysis.
CD8+ T cells contribute to arterial aging in mice.
ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion.
CXCR2-Dependent Infiltration of Tumor-Associated Neutrophils Is Linked to Enhanced CD8+ T Cell Effector Function and Reduced Lung Metastasis in 4T1 Breast Cancer.
Comparing Heparin and Heparin Mimetics in Targeting Immunomodulatory Proteins from Platelets to Activate T Cell-Dependent Immune Response in Oncology.
Tumor Core-Edge Divergence in T-Cell Exhaustion and Clonal Expansion in HPV-Related Cervical Squamous Cell Carcinoma Unveiled by Simultaneous Single-Cell RNA and TCR Sequencing.
Peripheral vaccination-induced brain-resident memory CD8+ T cells durably protect mice against intracranial malignancy.
Therapeutic strategies of metabolic reprogramming in non-small cell lung carcinoma.
Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.
A methodological approach for complex mixture aqueous solution analysis by ATR-FTIR spectroscopy.
Metabolic regulation of tumor-associated macrophage function and immunotherapy in cancer.
Immune signaling and function in neurodegeneration.
Advances in predicting T cell epitope recognition for cancer immunotherapy.
Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.
Purine salvage pathway protects CD8+ T cells from metabolic stress.
Solute Carrier Transporters in Tumor Metabolism and Tumor Immunity.
SpaHE-Infil: A spatial heterogeneity framework for decoding TME infiltration from H&E-stained slides.
Single-cell RNA sequencing analysis reveals cellular heterogeneity and immune microenvironment dynamics in colorectal cancer.
Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.
[Impact of HIF-1α-expressing Cellular Subpopulations on Lymph Node Metastasis  and Postoperative Recurrence in Non-small Cell Lung Cancer].

J Immunother Cancer. 2026 Apr 12. pii: e014041. [Epub ahead of print]14(4):

Stem-like PD-1+TCF-1+ CD8+ T cells result from helpless priming and rely on CD4+ T-cell help to complete their cytotoxic effector differentiation.

Julia Busselaar, Douwe M T Bosma, Mo D Staal, Xin Lei, Yanling Xiao, Jannie Borst.

   BACKGROUND: Antigen-specific CD8+ T cells can be in a stem-like programmed cell death protein-1 (PD-1)+TCF-1+ differentiation state that progresses into terminal exhaustion in cancer and chronic infection. These stem-like cells are important, since they are the responders to PD-1 targeted immunotherapy and a potential resource for antitumor immunity.
METHODS: We use a mouse vaccination model to delineate by spectral flow cytometry and single-cell RNA sequencing the effects of CD4+ T-cell help during priming on the differentiation fate of stem-like CD8+ T cells. We use bioinformatic analysis to extrapolate our data to mouse models of cancer and chronic infection. We next explore CD8+ T-cell differentiation states and delivery of CD4+ T-cell help in the immunogenic MC38 tumor model.
RESULTS: Upon vaccination in the absence of help signals, stem-like CD8+ T cells do not further differentiate and accumulate in the draining lymph node. When help signals are delivered, stem-like CD8+ T cells proliferate and differentiate into circulating cytotoxic effector cells. Stem-like CD8+ T cells raised by vaccination in presence or absence of CD4+ T-cell help have an identical transcriptome, which they share with stem-like CD8+ T cells defined in mouse models of cancer and chronic infection. The immunogenic MC38 tumor harbors endogenous helper epitopes, but primes stem-like CD8+ T cells rather than helped cytotoxic effectors. Therapeutic vaccination with endogenous helper epitopes does not improve MC38 tumor control. Intratumoral expression of strong, exogenous helper epitopes as present in our vaccine improves tumor control, but does not efficiently convert stem-like tumor-specific CD8+ T cells into helped cytotoxic effectors.
CONCLUSIONS: Our data argue that stem-like CD8+ T cells are helpless cells that lie at the bifurcation point of CD8+ T-cell effector and exhaustion trajectories. Even though the immunogenic MC38 tumor expresses helper epitopes, it primarily raises stem-like CD8+ T cells, indicating that help delivery is impaired in this tumor context. Promoting the efficient delivery of help signals to stem-like tumor-specific CD8+ T cells to drive their expansion and differentiation into cytotoxic effectors is therefore an important therapeutic challenge in cancer and other conditions that lead to T-cell exhaustion.

Keywords:  Immunotherapy; T cell; Tumor infiltrating lymphocyte - TIL; Vaccine; co-inhibitory molecule

DOI:  https://doi.org/10.1136/jitc-2025-014041
Front Immunol. 2026 ;17 1775837

The construction of CD8+ T cell-associated molecular subtypes in esophageal squamous cell carcinoma reveals tumor heterogeneity, tumor microenvironment, and immunotherapy.

Sinan Cao, Hao Jiang, Yang Li, Ke Yang, Lili Tian, Linwei Li.

   Background: Esophageal squamous cell carcinoma (ESCC) is a cancer that is common worldwide. Its morbidity and mortality rates remain high, seriously threatening human health. In the tumor microenvironment (TME), CD8+ T cells undergo a series of dynamic changes that have important implications for tumor progression and the efficacy of immunotherapy. Our research aims to construct novel molecular subtypes through the gene expression profiling of CD8+ T cells during differentiation and to predict the prognostic and therapeutic effects in ESCC patients.
Methods: In the single-cell sequencing (scRNA-seq) analysis, we clustered and visualized cell subsets using the Seurat package, removed batch effects between samples using the Harmony package, and performed pseudo-time analysis of CD8+ T cells using the Monocle2 package. In the bulk-RNA analysis, non-negative matrix factorization (NMF) was applied to construct molecular subtypes, and the unique expression of molecular subtypes in prognostic assessment, biological processes, genomic variation, and immune microenvironment composition was explored. The drug sensitivity of different subtypes was further studied. The causal relationship between gene expression during CD8+ T cell differentiation and ESCC occurrence was inferred using Mendelian Randomization (MR) analysis. In addition, the biological functions of key genes were further explored by in vitro cellular experiments.
Results: Based on the genes during CD8+ T cell differentiation, we identified three molecular subtypes with different clinical outcomes. To ensure the robustness and reproducibility of the molecular subtypes, we used the GSE53625 cohort for validation. Among them, the C1 subtype showed higher genomic variation, and its patients had significantly worse prognoses than the C2 and C3 subtypes. It is worth noting that the C3 subtype exhibits an "immune-heat" phenotype, which is accompanied by a large number of immune cell infiltrates, up-regulated immunological checkpoint molecules, and greater sensitivity to immune therapy. In addition, we have screened a series of potential therapeutic drugs, which provides strong support for future clinical translational research. Finally, the results of Mendelian randomization analysis indicated that the RHOB gene could increase the risk of ESCC development. In addition, in vitro cellular assays such as CCK-8, scratch assay and Transwell verified that RHOB could promote the proliferation, migration and invasion of ESCC cells in vitro.
Conclusion: This study constructed molecular subtypes related to CD8+ T cells and analyzed in depth the biological characteristics, genomic variation, and role of these three molecular subtypes in the tumor microenvironment and immunotherapy. These molecular subtypes allow us to more accurately identify patient groups and thus provide more effective treatment strategies for ESCC patients. In addition, this study identified RHOB as a novel biomarker for esophageal squamous cell carcinoma and verified that RHOB was associated with proliferation, migration and invasion of ESCC by in vitro cellular assays.

Keywords:  CD8+ T cell; RhoB; esophageal squamous cell carcinoma; heterogeneity; immunotherapy; single-cell RNA-seq

DOI:  https://doi.org/10.3389/fimmu.2026.1775837
Amino Acids. 2026 Apr 17.

Targeting the amino acid metabolic axis: the Achilles' heel of tumor cells.

Zheyu Hu, Yiwei Wang, Qian Ma.

  Cancer is characterized by profound reprogramming of its metabolic programs, with the unending demand for exogenous amino acids by tumor cells serving as a hallmark manifestation. While this high dependency supports rapid proliferation, it exposes a critical vulnerability: disruption of amino acid supply can specifically trigger metabolic catastrophe in cancer cells. Furthermore, tumor cells exploit this metabolic reprogramming to deplete key amino acids in the microenvironment, thereby suppressing T-cell function and facilitating immune evasion. This review systematically elucidates therapeutic strategies targeting four critical amino acid metabolic axes (glutamine, arginine, tryptophan, and methionine). We delve into how inhibition of glutamine metabolism disrupts tumor bioenergetics, how arginine deprivation selectively targets cells with synthetic defects, and how methionine restriction interferes with key epigenetic regulation. Additionally, we explore interventions for these four amino acid metabolic axes to reverse immunosuppression. Convincing preclinical and clinical evidence demonstrates that these strategies, whether as monotherapy or rational combinations with conventional treatments, exhibit significant antitumor efficacy and substantial clinical translation potential. By integrating metabolic and immunological perspectives and critically assessing translational challenges, this review aims to provide a roadmap for future development of precision combination strategies capable of overcoming drug resistance and reshaping the immune microenvironment.

Keywords:  Amino acid metabolic reprogramming; Combination therapy; Immunosuppression; Metabolic addiction; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00726-026-03522-4
Bioelectrochemistry. 2026 Apr 07. pii: S1567-5394(26)00088-5. [Epub ahead of print]171 109302

Molecularly imprinted polymer-based electrochemical sensor for L-tyrosine competition-mediated T cell exhaustion.

Zhen Peng, Yihao Long, Zhihao Tu, Muhammad Tahir, Liang He.

  Nutrition competition exists in the tumor microenvironment (TME), which is considered as an important factor of T cell exhaustion. Various amino acids are the targets for both tumor cells and T cells, including L-Tyr, which plays an essential role in normal function of T cells. Herein, a novel sensing interface of MIP/Fc/PEDOT:PSS-PPy/graphite/Au established on a PCB substrate, was proposed for L-Tyr detection. This sensor was systematically characterized and showed excellent repeatability, stability, reproducibility, and specificity. Meanwhile, the sensor exhibited good detection capability, with a linear range of 1 nmol/L to 1 mmol/L, a limit of detection of 1.62 × 10-11 mol/L, and a sensitivity of 97.14 μA/(mol/L). An in-vitro co-culture model of T cells and tumor cells was established to mimic the TME, and its culture medium was used as real samples for L-Tyr determination via the proposed sensor. The results demonstrated that the failure of L-Tyr competition by T cells in the TME was a vital cause of their exhaustion, which was further validated by the IL-2 expression of T cells within the TME using ELISA. Collectively, our study is expected to provide a new strategy for tumor treatment, by supplementing exogenous amino acids to alleviate T cell exhaustion.

Keywords:  L-tyrosine; MIP sensor; Microfluidics; T cell exhaustion

DOI:  https://doi.org/10.1016/j.bioelechem.2026.109302
Front Immunol. 2026 ;17 1788922

Endometrial immune dysregulation shapes CD8+ T cell mediated reproductive outcomes in recurrent implantation failure: an integrated mechanistic and predictive analysis.

Shan Jiang, Yeqing Fu, Xiufeng Lin, Qingni Li, Zhibin Huang, Cong Zhou, Yecheng Zou, Yutong Li.

   Background: The recurrent implantation failure (RIF) remains a major clinical challenge in assisted reproduction. While endometrial immune dysregulation is implicated, its specific role and interaction with clinical factors are poorly defined. The lack of integrated, multimodal predictive models that combine clinical history with immune profiling limits personalized management.
Methods: This study conducted a retrospective cohort study of 110 RIF patients, collecting comprehensive clinical and immune parameters. Traditional statistics and machine learning were employed to identify key predictors and build predictive models. Model interpretability was assessed using SHAP analysis, and causal pathways were explored via mediation analysis and restricted cubic splines.
Results: Previous implantation failure number was the strongest negative predictor (aOR = 0.74, 95% CI 0.60-0.91, P = 0.004). Endometrial CD8+ T cell proportion exhibited a positive, threshold-dependent effect: above 2.0%, each 1% increase raised the odds of success by 25% (aOR = 1.25, 95% CI 1.03-1.52, P = 0.025). Embryo quality was an independent positive predictor (aOR = 1.62, 95% CI 1.04-2.53, P = 0.033). Machine-learning modeling (XGBoost) achieved an AUC of 0.762 (95% CI 0.734-0.790). Mediation analysis revealed that 22.8% of the total effect of immune dysregulation on outcome was mediated through CD8+ T cells. Furthermore, the protective effect of CD8+ T cells was significantly enhanced in patients with severe immune disorder (interaction P = 0.034).
Conclusion: This integrated clinical-immune signature underscores the pivotal, threshold-dependent role of endometrial CD8+ T cells and the cumulative burden of previous failures in RIF. The internally validated machine-learning model offers a prognostic tool, and the elucidated CD8+ T cell-mediated pathway suggests a target for immunomodulation, advancing the precision management of RIF.

Keywords:  CD8+ T cells; immune disorder; implantation failure number; machine learning; predictive modeling; recurrent implantation failure

DOI:  https://doi.org/10.3389/fimmu.2026.1788922
J Immunol. 2026 Apr 15. pii: vkag060. [Epub ahead of print]215(4):

CD8+ T cells contribute to arterial aging in mice.

David J Buckley, Sogol Zahedi, Alexandra Canizales, Nathan E Cuellar, Kidist Bogale, Katherine A Smith, Konner J Terrebonne, Sunita Sharma, Blessy Joseph, Jody L Greaney, Daniel W Trott.

  We have previously reported that T cells accumulate in the arteries of old mice and mechanistically contribute to the development of age-related arterial dysfunction. However, the specific T cell subtype that is the primary contributor to arterial aging is unknown. There is substantial evidence that CD8+ T cells are more susceptible to the effects of aging compared with their CD4+ counterparts. We hypothesized that CD8+ T cell-specific depletion would ameliorate large-artery stiffness and augment endothelium-dependent dilation in old mice but not in young mice. We observed that old mice exhibited a greater accumulation of CD8+, but not CD4+, T cells in the aorta and mesentery compared with their young counterparts. Further, pharmacological depletion of CD8+, but not CD4+, T cells resulted in lower aortic stiffness and blunted aortic collagen. In addition, old CD8+, but not CD4+, depleted mice demonstrated augmented endothelium-dependent dilation via greater nitric oxide bioavailability. These data indicate that CD8+ T cells are the specific T cell subtype that contributes to age-related arterial dysfunction.

Keywords:  adaptive immunity; aortic stiffness; nitric oxide bioavailability

DOI:  https://doi.org/10.1093/jimmun/vkag060
Cancer Immunol Res. 2026 Apr 13.

ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion.

Sujit Kashyap, Jun Hyung Sin, Sophia M Guldberg, Jacqueline L Yee, Maya Lopez-Ichikawa, Sloan H Phillips, Matthew H Spitzer, Michael Waterfield.

CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells resulted in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Given the decreased T cell terminal exhaustion observed with Atf7ip-deficiency in CD8+ T cells, this may be one mechanism that leads to decreased tumor burden. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0816
Int J Mol Sci. 2026 Mar 30. pii: 3143. [Epub ahead of print]27(7):

CXCR2-Dependent Infiltration of Tumor-Associated Neutrophils Is Linked to Enhanced CD8+ T Cell Effector Function and Reduced Lung Metastasis in 4T1 Breast Cancer.

Tiantian Li, Teizo Yoshimura, Miao Tian, Gakushi Nishida, Chunning Li, Masayoshi Fujisawa, Toshiaki Ohara, Akihiro Matsukawa.

  Triple-negative breast cancer (TNBC) is characterized by prominent neutrophil infiltration; however, its significance remains controversial. Here, we investigated the role of neutrophil chemoattractant receptors in TNBC progression and metastasis. In contrast to wild-type (WT), Fpr1-/-, and Fpr2-/- mice, neutrophils were almost completely absent in 4T1 tumors from Cxcr2-/- mice, indicating a dominant role for CXCR2 in the recruitment of tumor-associated neutrophils, leading us to use Cxcr2-/- mice for further studies. Primary tumor growth was comparable between WT and Cxcr2-/- mice, whereas lung metastasis was significantly increased in Cxcr2-/- mice, with reduced expression of inflammatory cytokines, chemokines and cytotoxic molecules, including granzyme B and perforin, in primary tumors and metastatic lungs of Cxcr2-/- mice. In vitro, WT, but not Cxcr2-/-, neutrophils enhanced CD8+ T cell activation, partly via ICAM-1, and directly induced tumor cell death, supporting their anti-tumor function. To assess clinical relevance, transcriptomic data were analyzed. High neutrophil infiltration combined with elevated CXCR2 expression, and to a lesser extent CXCR1 expression, was associated with improved prognosis in patients with basal-like BC that largely overlaps with TNBC. Collectively, these findings suggest that CXCR2-mediated neutrophil recruitment exerts protective, anti-tumor effects and may represent a new prognostic marker for TNBC patients.

Keywords:  CD8+ T cells; breast cancer; chemokine receptors; chemokines; neutrophils; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27073143
ACS Pharmacol Transl Sci. 2026 Apr 10. 9(4): 954-965

Comparing Heparin and Heparin Mimetics in Targeting Immunomodulatory Proteins from Platelets to Activate T Cell-Dependent Immune Response in Oncology.

Katrin Nekipelov, Sven Otto, Maximilian Henseler, Sabine Vidal-Y-Sy, Abdullah Al Nahain, Christian Gorzelanny, Vito Ferro, Gerd Bendas.

  Platelets play a crucial role in the hematogenous metastasis of cancer. Beyond their mechanical function of forming a protective cloak around circulating tumor cells, which can be antagonized by heparin, activated platelets release various immunomodulatory components. Based on a proteome profiling of releasates, we address the immunosuppressive activities of TGF-β1 and MMP2 to CD4+ and CD8+ T cells in several in vitro assays and compare heparin and synthetic heparin mimetics in targeting them to reverse immunosuppression of platelets in an oncological context. Whole platelet releasates promote the differentiation of naïve human CD4+ T cells into regulatory T cells, while heparin mimetics outperform unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in attenuating this effect. When addressing TGF-β1 as an immunosuppressive component in this CD4+ T cell approach, the lower molecular weight of heparin appears favorable, reflected by higher binding affinities to TGF-β1 in biosensor analyses. The impact of TGF-β1 on reducing the release of cytolytic perforin and granzyme B from CD8+ T cells is reversed by heparin and mimetics in different intensities, favoring smaller molecular sizes. Furthermore, heparin promoted CD8+ T cell binding to activated endothelial cells in a microscopic flow chamber approach in the presence of releasates, indicating increasing CD8+ T cell activity. Additionally, the mimetics significantly reduced the activity of MMP2 compared to LMWH, related to their direct binding and thus deactivating this enzyme. These studies provide insights into immunosuppression of platelets and functional interference thereof by heparin and emphasize heparin mimetics for antagonizing these activities in the context of cancer immunology.

Keywords:  MMP2; TGF-β1; cancer; immune cells; metastasis; platelets

DOI:  https://doi.org/10.1021/acsptsci.5c00722
J Med Virol. 2026 Apr;98(4): e70912

Tumor Core-Edge Divergence in T-Cell Exhaustion and Clonal Expansion in HPV-Related Cervical Squamous Cell Carcinoma Unveiled by Simultaneous Single-Cell RNA and TCR Sequencing.

Tianyu Lei, Fuhao Wang, Shuomin Zhang, Liang Zhang, Hongfu Wei, Yixuan Li, Qingyu Huang, Xiang Liu, Liangbin Xia, Cong Wang, Chao Liu, Qinyong Hu.

  Tumor spatial architecture significantly influences immune responses, but the impact of regional variations on T cell exhaustion and clonality in human papillomavirus (HPV)-related cervical squamous cell carcinoma (CESC) remains poorly understood. Using single-cell RNA sequencing (scRNA-seq, n = 13) and TCR sequencing (scTCR-seq, n = 9), this study profiled T cells from paired tumor core and edge samples of patients with CESC. This was supplemented by bulk RNA-seq data (n = 41), TCGA datasets from three cancer types (CESC, head and neck squamous cell carcinoma, and lung squamous cell carcinoma), and scRNA-seq data from colorectal cancer for broader validation. We found that CD8+ T cells, natural killer T (NKT) cells, and γδ T cells in the tumor core exhibited higher inhibitory and cytotoxicity scores, while CD4+ T cells showed increased regulatory T (Treg) and cytotoxic features in the tumor core. Bulk RNA-seq data confirmed elevated inhibitory and cytotoxic scores in the tumor core relative to the edge. Additionally, four subsets of exhausted CD8+ T cells (CD8+ Tex) were identified, including a stress-associated subset characterized by heat shock protein (HSP) family gene expression, which was validated by immunofluorescence and inversely correlated with survival in patients with CESC undergoing radiotherapy. TCR analysis revealed clonal expansion and reduced clonal diversity in the tumor core. Notably, CD8+ Teff-CD160 cells displayed substantial clonal sharing across regions and were associated with a favorable prognosis. Overall, our findings highlight distinct T cell states between the tumor core and edge in HPV-related CESC, offering insights into prognostic biomarkers and potential therapeutic targets.

Keywords:  T cell exhaustion; TCR clonality; cervical squamous cell carcinoma; scRNA‐seq; spatial heterogeneity

DOI:  https://doi.org/10.1002/jmv.70912
J Clin Invest. 2026 Apr 15. pii: e197812. [Epub ahead of print]136(8):

Peripheral vaccination-induced brain-resident memory CD8+ T cells durably protect mice against intracranial malignancy.

Madison R Mix, Cassie M Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L Pewe, Sunny C Huang, Rui He, Cori E Fain, Mohammad Heidarian, Lisa S Hancox, Sahaana A Arumugam, Terry G Beltz, Fang Jin, Aaron J Johnson, Calvin S Carter, Noah S Butler, Aliasger K Salem, Vladimir P Badovinac, John T Harty.

  Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Keywords:  Immunology; Memory; Neuroscience; Oncology; T cells

DOI:  https://doi.org/10.1172/JCI197812
Ann Med. 2026 Dec;58(1): 2652110

Therapeutic strategies of metabolic reprogramming in non-small cell lung carcinoma.

Jiajun Liu, Fenhong Qian.

   BACKGROUND: Non-small cell lung carcinoma (NSCLC) remains a leading cause of cancer-related mortality worldwide, with existing therapies frequently hindered by drug resistance and immunosuppression. Metabolic reprogramming (glycolysis, lipid metabolism, and amino acid metabolism) has emerged as a core hallmark driving NSCLC progression, tumor microenvironment (TME) remodeling, and treatment failure, transcending the classical Warburg effect to involve intricate cross-talk between cancer cells and stromal components.
DISCUSSION: This review systematically synthesizes the latest insights into the regulatory mechanisms of metabolic reprogramming in NSCLC, highlighting how dysregulated glycolytic flux, altered lipid synthesis/oxidation, and adaptive amino acid utilization collectively sustain tumor growth, invasion, and immune escape. We critically examine the interplay between metabolic reprogramming and driver gene mutations (EGFR/KRAS/ALK), unraveling how mutation-specific metabolic adaptations contribute to targeted therapy resistance, and explore the role of metabolic heterogeneity in shaping treatment responses. Furthermore, we dissect actionable therapeutic strategies that target metabolic vulnerabilities, including immunotherapy synergies (e.g. PD-1 inhibitors combined with PKM2/ferroptosis targeting, metabolically modified CAR-T cells), subtype-specific targeted interventions (e.g. DPP4/GFPT2/PFKFB3 inhibitors reversing mutation-driven metabolic resistance), and chemotherapy sensitization approaches (e.g. CPT1A/GLUD1 inhibitors overcoming cisplatin resistance via suppressing metabolic compensation).
CONCLUSION: This review underscores the clinical potential of targeting metabolic reprogramming to address unmet therapeutic needs, proposing synergistic regimens and personalized metabolic therapy frameworks that hold promise for improving NSCLC patient outcomes.

Keywords:  Metabolic reprogramming; NSCLC; tumor progression and metastasis

DOI:  https://doi.org/10.1080/07853890.2026.2652110
Front Immunol. 2026 ;17 1736082

Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.

Yuzhe Yin, Chaosheng Yan, Xinyu Pei, Jingjing Rao, Ling Wu, Yuzheng Xue, Haowen Sun, Yingyue Sheng.

  Amino acid metabolic reprogramming is an important component of immunometabolism. In addition to providing biosynthetic substrates and energetic support for macrophages, distinct amino acid metabolic pathways can also reshape the inflammatory and reparative functional states of macrophages by regulating redox homeostasis, epigenetic modifications, signal transduction, and the accumulation of metabolic intermediates. Despite rapid progress in this field, there remains a lack of systematic integration regarding how key metabolic axes, including arginine metabolism, tryptophan catabolism, and glutamine metabolism, coordinately or antagonistically drive macrophage functional reprogramming, as well as the conservation, heterogeneity, and translational significance of these changes across different autoimmune-related diseases. This review summarizes the roles of arginine, tryptophan, glutamine, branched-chain amino acid, serine/glycine/threonine, aspartate/asparagine, and sulfur-containing amino acid metabolism in the dynamic spectrum of macrophage polarization, and further outlines recent advances in systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, psoriasis, autoimmune hepatitis, and vasculitis. This review emphasizes that amino acid metabolism is not an isolated regulatory module, but rather part of an interconnected network that, together with glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle anaplerosis, one-carbon metabolism, and lipid metabolism, determines macrophage fate. Given the existing differences in evidence strength and metabolic phenotypes among in vitro systems, animal models, and human studies, caution is still required when extrapolating these conclusions to clinical settings. Overall, therapeutic interventions targeting amino acid metabolism may provide novel biomarkers and treatment strategies for autoimmune-related diseases, but their clinical translation still depends on higher-resolution human validation and mechanism-oriented precision studies.

Keywords:  arginine metabolism; glutamine metabolism; immunometabolism; metabolic reprogramming; therapeutic targeting; tryptophan catabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1736082
Chin Herb Med. 2026 Apr;18(2): 439-451

A methodological approach for complex mixture aqueous solution analysis by ATR-FTIR spectroscopy.

Lingyu Han, Qun Zhou, Hang Yin, Suqin Sun.

   Objective: To develop an in situ, nondestructive approach for simultaneously acquiring overall structural and intermolecular interaction information of multiple components in complex aqueous mixtures without sample separation.
Methods: In this paper, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) was utilized to detect and analyze the juice and decoction (clinical application forms) of different processed products of a traditional Chinese medicine (TCM)-Rehmanniae Radix (Dihuang in Chinese). By the analysis of IR and the second derivative IR (SD-IR) spectra, the spectral structure information of water, organic acid, stachyose, glucose, galactose, fructose, manninotriose, amino acid and protein in the mixture system was extracted through non separation fingerprint characteristic.
Results: A large number of in situ dynamic tracked IR spectra, obtained by ATR-FTIR and TimeBase software, were used to excavate the changes of absorption peak intensity (structural analysis) and diffusion velocity (time resolution) in the process of liquid adsorption-diffusion. The results indicated the coexistence of free hydroxyl groups, intermolecular hydrogen bonds, and intramolecular hydrogen bonds, analyzed by two-dimensional correlation infrared spectroscopy (2DCOS-IR), confirming their complex and dynamic hydrogen-bonding network structures. Furthermore, spectral analysis revealed interactions among the various active components in the mixtures, providing a microstructural basis for interpreting their holistic effects.
Conclusion: This study provided a theoretical basis for the efficacy and pharmacologic mechanism of different processed forms of TCM from the perspective of physical chemistry. Also, it discussed how to carry out nondestructive and in situ dynamic tracking of complex mixture aqueous solution system, and how to study the timeliness, synergy and interaction of samples.

Keywords:  ATR-FTIR; complex mixture aqueous solution; dynamic tracking; hydrogen bond; interaction between components; methodological approach; overall analysis; traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.chmed.2026.01.001
Cancer Biol Med. 2026 Apr 13. pii: j.issn.2095-3941.2025.0626. [Epub ahead of print]

Metabolic regulation of tumor-associated macrophage function and immunotherapy in cancer.

Mingyue Zhao, Rui Chen, Ping Gao.

  Tumor-associated macrophages (TAMs), essential components of the tumor immune microenvironment (TIME), undergo metabolic reprogramming as part of functional adaptation. Tumor cells modulate TAMs through multiple mechanisms, including metabolic cross-feeding, cytokine production, extracellular vesicles, tumor-derived proteins (such as GRP78) and pathogen-associated patterns (such as Lipopolysaccharide) signaling mediators. In turn, metabolic alterations in TAMs fine-tune TAM function via intricate signaling networks with outcomes that vary across cancer types. These functional and phenotypic shifts enable TAMs to influence malignant cells and other TIME components, such as T cells, NK cells, and fibroblasts, through the secretion of inflammatory factors and changes in surface marker expression. This process establishes an extensive network of interconnected cellular crosstalk. In this review the metabolic alterations-intracellular signaling-TAM biology axis is linked to cancer progression contributions and the implications for immunotherapy across diverse malignancies. Building on these insights, current preclinical and clinical studies with a focus on TAMs were surveyed and the advantages and challenges of TAM-targeted therapeutic strategies were systematically evaluated. We anticipate that these perspectives will spur further investigation into TAM-specific immune targets and accelerate the development of next-generation cancer immunotherapies.

Keywords:  Tumor-associated macrophage; immunotherapy; metabolic rewiring; tumor microenvironment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0626
J Clin Invest. 2026 Apr 15. pii: e199850. [Epub ahead of print]136(8):

Immune signaling and function in neurodegeneration.

Yvonne L Latour, Dorian B McGavern.

Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.

DOI: https://doi.org/10.1172/JCI199850
Nat Cancer. 2026 Apr 16.

Advances in predicting T cell epitope recognition for cancer immunotherapy.

David Gfeller, Julien Racle, Alexandre Harari, Giancarlo Croce.

T cell recognition of malignant cells is central to cancer immunotherapy. This process is elicited by interactions between T cell receptors (TCRs) and antigenic peptides displayed on major histocompatibility complex molecules. Sequencing technologies enable characterization of genomic, transcriptomic and epigenetic alterations that can give rise to epitopes in cancer cells, alongside TCR repertoire profiling in T cells. An important challenge is to determine which peptides are recognized by T cells and which TCRs mediate this recognition. This Perspective highlights how technological and computational advances have improved epitope predictions, shed light on TCR-epitope recognition and could help leverage TCR repertoires for therapeutic innovations in cancer immunotherapy.

DOI: https://doi.org/10.1038/s43018-026-01144-z
Int J Mol Sci. 2026 Mar 31. pii: 3169. [Epub ahead of print]27(7):

Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.

Jie Ren, Zhengrong Gong, Yutong Zhong, Ruipei Xiao, Khadija Urooj, Yuan Gao, Enguang Bi, Handuo Wang.

  Adoptive T cell therapy (ACT) remains limited in solid tumors by poor T cell persistence within the metabolically hostile tumor microenvironment (TME). Although IL-9-producing CD8+ T cells (Tc9) consistently demonstrate superior antitumor efficacy compared with conventional Tc1 cells, the selective pressures that shape their functional advantage remain unclear. Here, we show that effective ACT-mediated tumor control is accompanied by a marked increase in intratumoral extracellular ATP (eATP), representing a common metabolic consequence of tumor cell destruction. Despite comparable ATP accumulation following Tc1 or Tc9 treatment, these subsets exhibit strikingly distinct responses to ATP stress. Tc1 cells are highly susceptible to ATP-induced apoptosis, whereas Tc9 cells display intrinsic resistance, resulting in superior in vivo persistence. Mechanistically, Tc9 cells actively convert ATP signaling into enhanced mitochondrial fitness, characterized by increased oxidative phosphorylation and spare respiratory capacity. ATP exposure further drives Tc9 cells toward a tissue-resident memory (TRM) phenotype through activation of the TGF-β signaling axis. Transcriptomic and molecular analyses reveal that purinergic signaling pathways, including elevated expression of the ATP receptor P2RX7, are intrinsically enriched in Tc9 cells and are further amplified upon ATP stimulation. Collectively, our findings identify extracellular ATP as a metabolic lineage selection signal in ACT, demonstrating that ATP stress preferentially stabilizes metabolically resilient Tc9 cells by linking purinergic sensing to mitochondrial remodeling and TRM programming, thereby providing a conceptual basis for enhancing the persistence and efficacy of engineered T cell therapies in solid tumors.

Keywords:  ATP; IL-9+ CD8+ T cells; adoptive T cell therapy (ACT); cancer immunotherapy; mitochondria; resident memory T cells (TRM)

DOI:  https://doi.org/10.3390/ijms27073169
Nat Immunol. 2026 Apr 13.

Purine salvage pathway protects CD8+ T cells from metabolic stress.

Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-Ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan.

Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.

DOI: https://doi.org/10.1038/s41590-026-02491-w
Chem Biol Interact. 2026 Apr 14. pii: S0009-2797(26)00192-4. [Epub ahead of print] 112084

Solute Carrier Transporters in Tumor Metabolism and Tumor Immunity.

Miaobo Chen, Jie Xu, Heling Ma, Jinlong Qin, Jiajing Cheng, Jia Lv.

  Research on solute carrier (SLC) transporters has become a well-established field, revealing the functional roles of these transmembrane proteins in cancer biology. SLC transporters are transmembrane channel proteins that mostly contain 7 to 12 transmembrane domains and mediate numerous essential physiological functions, including the transportation of metabolites (such as glucose, amino acids, and lipids), signal transduction, immune cell interaction, and the regulation of mitochondrial homeostasis. The expression of SLC transporters shows tissue, disease, and spatiotemporal specificity, and accumulating evidence indicates that SLC transporters are closely associated with pathological conditions, particularly tumor prognosis. Due to the phylogenetic or species conservation, tumor tissue expression specificity, and the ability to functionally target specific pathways of SLC transporters, SLCs have the potential to serve as biomarkers for tumor diagnosis, treatment, and prognosis. SLC transporters play a significant role in tumor metabolism and tumor immunity. They not only influence the metabolism and immune regulation of tumor cells but also affect the metabolism and immune responses of essential components of the tumor microenvironment, such as T cells, natural killer cells, and macrophages. Here, we give a thorough review of the functions that SLCs play in tumor immunity and tumor metabolism, highlighting their impact on immune cell function in the tumor microenvironment and tumor cellular metabolic reprogramming. We also provide an overview of the structure of SLCs, the pharmacology of SLCs, and the current advancements in anticancer therapies targeting SLCs, with particular emphasis on those demonstrating clinical efficacy. In addition to synthesizing recent evidence, this review discusses the challenges in the field of SLC transporters and proposes future research directions.

Keywords:  cancer immunity; cancer metabolism; pharmacology; solute carrier transporter; structure; targeted therapy

DOI:  https://doi.org/10.1016/j.cbi.2026.112084
iScience. 2026 Apr 17. 29(4): 115155

SpaHE-Infil: A spatial heterogeneity framework for decoding TME infiltration from H&E-stained slides.

Fang Wang, Hejia Xu, Xue Wang, Mengyin Wu, Sisi Ding, Lian Duan, Chen Yang, Jiaxuan Li, Xiaosong Ge, Yan Qin, Xiaowei Qi, Yong Mao.

  The spatial distribution of immune cells in the tumor microenvironment (TME) is a key determinant of immunotherapy response, while current methods are limited by sequencing dependence and restricted spatial resolution. We developed SpaHE-Infil, a multimodal computational framework integrating spatial transcriptomics and whole-slide images to train a Random forest model, extracting morphological, textural, and density features to identify 12 core TME cell types in situ, with dynamic calibration correcting immune cell proportion biases in clinical samples. Cross-cancer validation confirmed its accurate spatial cell distribution prediction, consistent with mIHC and canonical deconvolution algorithms. In clinical cohorts, TME immune infiltration stratification via H&E images predicted enhanced immunotherapy response and prolonged recurrence-free survival across multiple cancers. This framework provides a clinically applicable tool for spatial TME characterization, supporting tumor immunology research, and precision immunotherapy practice.

Keywords:  Bioinformatics; Cancer; Medicine; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.115155
Int J Biol Markers. 2026 Apr 12. 3936155261441324

Single-cell RNA sequencing analysis reveals cellular heterogeneity and immune microenvironment dynamics in colorectal cancer.

Jin-Liang Zhu, Hong-Jian Gao, Lu-Ji Qiao, Rong-Xiang Si, Xing-Dong Li, Yi You, Zhi-Tao Yin.

  BackgroundDespite treatment advances, prognoses of patients with advanced colorectal cancer remain poor. The limited effectiveness of programmed cell death protein 1 (PD-1) blockade immunotherapy in a subset of patients necessitates a deeper understanding of the colorectal cancer microenvironment. This study aimed to identify new therapeutic targets and potential biomarkers by investigating CD8 + CD101hiTim3+ (CCT) T cells and their progenitors in colorectal cancer, and their association with immunotherapy response at the transcriptomic level.MethodsWe used single-cell sequencing data and The Cancer Genome Atlas database for comprehensive bioinformatics analysis, including single-cell sequencing data analysis, Gene Set Variation Analysis, pseudotime analysis, cell communication analysis, and construction and validation of a prognostic model.ResultsKey findings include the identification and annotation of various T-cell subtypes in colorectal cancer, construction of a pseudotime trajectory of CCT T cells and their progenitors showing dynamic gene expression changes, and enhanced interactions between CCT T cell progenitors and other cells in the PD-1 immunotherapy group. We developed and validated a prognostic model comprising 15 gene features with strong prognostic stratification performance, revealing that high-risk patients exhibit transcriptomic associations with potentially reduced responses to immune checkpoint inhibitors (ICIs). Pathway enrichment analysis highlighted critical pathways, including leukocyte adhesion and T cell activation, indicating complex influences on disease progression and treatment responses within the colorectal cancer immune landscape.ConclusionsThis study emphasizes the potential importance of targeted therapies that modulate immune interactions and functional states to improve colorectal cancer prognosis, particularly in high-risk patients who show an association at the transcriptomic level with reduced ICI responsiveness.

Keywords:  T cell; immune checkpoint inhibitors; programmed cell death protein 1; tumor microenvironment

DOI:  https://doi.org/10.1177/03936155261441324
Amino Acids. 2026 Apr 14.

Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Jiaqi Fang, Jing Ling, Xinyue Liu, Yanbin Wang, Yongbiao Huang, Zhe Cao, Yanmei Zou, Hua Xiong.

  Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research.

Keywords:  Ammonia; CPS1; GLS1; Nitrogen metabolism; Tumor

DOI:  https://doi.org/10.1007/s00726-026-03517-1
Zhongguo Fei Ai Za Zhi. 2026 Feb 20. 29(2): 115-123

[Impact of HIF-1α-expressing Cellular Subpopulations on Lymph Node Metastasis  and Postoperative Recurrence in Non-small Cell Lung Cancer].

Fanghan Cao, Qianhui Chen, Liying Yang, Miaoqing Zhao, Xiaorong Sun, Ligang Xing.

   BACKGROUND: Non-small cell lung cancer (NSCLC) is associated with a high rate of postoperative recurrence, and conventional tumor-node-metastasis (TNM) staging does not fully reflect its biological heterogeneity. Hypoxia-inducible factor-1alpha (HIF-1α) plays a critical role in tumor progression and remodeling of the tumor immune microenvironment. However, the spatial distribution of HIF-1α and its prognostic significance in the context of different lymph node metastatic states remain unclear. This study aimed to investigate the densities of HIF-1α-expressing tumor cells, CD4+ T cells, and CD8+ T cells in the primary tumors of NSCLC patients, and to assess their associations with lymph node metastasis and postoperative recurrence.
METHODS: 256 formalin-fixed paraffin-embedded primary tumor specimens from NSCLC patients who underwent radical resection at Shandong First Medical University Affiliated Cancer Hospital between January 1, 2014 and December 31, 2018 were retrospectively collected. Tissue microarrays containing both tumor center (TC) and invasive margin (IM) regions were constructed and multiplex immunofluorescence staining [HIF-1α/CD4/CD8/cytokeratin (CK)/4',6-diamidino-2-phenylindole (DAPI)] were performed to quantitatively analyze the densities of HIF-1α-expressing tumor cells (HIF-1α+CK+), HIF-1α+CD4+ T cells and HIF-1α+CD8+ T cells. Mann-Whitney U tests were used to compare cellular density differences between N0 versus N1-2 groups and N1 versus N2 subgroups, while Cox proportional hazards regression models were employed to identify critical recurrence-associated factors.
RESULTS: The study ultimately included 256 patients with stage IA-IIIB NSCLC, with a median follow-up duration of 37.05 months, during which 87 cases (34.0%) experienced recurrence. Comparative analysis revealed that in both TC and IM regions, the N1-2 group exhibited significantly higher densities of HIF-1α+CK+ cells (P values: 0.039 and <0.001, respectively) and lower densities of HIF-1α+CD8+ cells (both P values: <0.001) compared to the N0 group, while no statistically significant differences were observed in the densities of HIF-1α+CK+ cells, HIF-1α+CD4+ cells, or HIF-1α+CD8+ cells between N1 and N2 subgroups within either TC or IM regions (all P>0.05). Multivariate Cox regression analysis showed that, among N0 patients, a low density of HIF-1α+CD8+ cells in the TC was an independent risk factor for recurrence in NSCLC patients [hazard ratio (HR)=1.998, 95%CI: 1.077-3.705, P=0.028]. In contrast, among N1 and N2 patients, the densities of HIF-1α+CK+ cells, HIF-1α+CD4+ T cells, and HIF-1α+CD8+ cells in both the TC and IM regions were not significantly associated with NSCLC recurrence.
CONCLUSIONS: In patients with NSCLC, lymph node metastasis is closely associated with alterations in the densities of HIF-1α-related cellular subpopulations in the primary tumor. A reduced density of HIF-1α+CD8+ cells in the TC of the primary lesion is significantly associated with postoperative recurrence in N0-stage NSCLC patients and may serve as a potential immunological marker for postoperative risk stratification.

Keywords:  CD8+ T cell; Hypoxia-inducible factor-1alpha; Lung neoplasms; Lymph node metastasis; Prognosis; Recurrence-free survival time; Tumor center

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2026.106.05