bims-stacyt 2025-11-16 papers

Int Immunol. 2025 Nov 12. pii: dxaf068. [Epub ahead of print]

Repetitive Fasting-Refeeding Enhances Metformin-Induced CXCR6+ CD8+T Cell Tumor Infiltration via VCAM-1 Upregulation on Normalized Vasculature During Refeeding.

Weiyang Zhao, Miho Tokumasu, Mikako Nishida, Natsumi Imano, Nahoko Yamashita, Heiichiro Udono.

Fasting is known to alter the circulation dynamics of immune cells, including T cells, by shifting them from peripheral tissues to the bone marrow (BM), where they enter a quiescent state to avoid starvation stress and acquire apoptosis resistance through upregulation of BCL2. Upon refeeding, these T cells exit the BM and return to circulation. In solid tumors, fasting-refeeding not only affects the trafficking of CD8+ T cells between tumors and their draining lymph nodes (dLNs); but also modulates the antitumor immune response. In this study, we investigated how metformin's antitumor responses are affected by repeated fasting-refeeding cycles. Metformin administration combined with weekly 48-hour fasting showed a synergistic antitumor effect, which was abolished by in vivo depletion of CD8+ T cells. Immunohistofluorescence staining showed that fasting reduced CD8+T cells in tumors and dLNs while increasing their presence in the BM; refeeding reversed this distribution. Refeeding also increased the expression of Ifng, Gzmb, Tnf, and Tbx21 in tumors. Likewise, Cxcr6, Cxcl16, and Vcam1 expression levels were elevated only upon refeeding. Notably, CXCR6 was exclusively expressed on CD62L- effector memory T cells (TEM). The antitumor effect induced by the combinational therapy was abolished by administration of an anti-VCAM-1 neutralizing antibody. Our findings demonstrate that combining metformin with fasting exerts a synergistic antitumor effect by recruiting CD8+ T cells-relocated to the BM during fasting-back to the tumor during refeeding, facilitated by enhanced VCAM-1 expression on normalized tumor vasculature.

Keywords: Bone Marrow; Calorie Restriction; Chemokine Receptors; Effector Memory T Cell (TEM); Tumor Microenvironment

DOI: https://doi.org/10.1093/intimm/dxaf068

EMBO Rep. 2025 Nov 10.

TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes the transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. Here, we evaluate the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME). Tmprss11b depletion significantly reduces tumor burden in immunocompetent mice and triggers an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model reveal an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Furthermore, utilizing ultra-pH-sensitive nanoparticle imaging and metabolite analysis, we identify regions of acidification, elevated lactate, and enrichment of immunosuppressive (M2-like) macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

Keywords: Hillock Cells; Immune Suppression; Lactate-mediated TME Acidification; Squamous Cell Lung Cancer; Transmembrane Serine Protease TMPRSS11B

DOI: https://doi.org/10.1038/s44319-025-00631-1

Cancer Commun (Lond). 2025 Nov 10.

Unfolded protein response kinase PERK supports survival and metastasis of circulating tumor cell clusters via SAM synthesis and H3K4me3-dependent PDGFB signaling.

Rui Tang, Yan Sun, Ao Deng, Jiahe Liu, Peijin Dai, Jing Chen, Chaoqun Deng, Hui Liu, Yuhang Hai, Yanran Tong, Yan-E Du, Manran Liu, Haojun Luo.

BACKGROUND: Metastasis is the leading cause of cancer-related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.
METHODS: CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient-derived xenograft (PDX), cell line-derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing (RNA-seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA-seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.
RESULTS: CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S-adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B (PDGFB) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway via platelet-derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.
CONCLUSIONS: Our findings revealed a PERK/MAT2A/PDGFB axis that confers adaptive survival capabilities to CTC clusters in the bloodstream. Targeting this survival signaling pathway represents a promising therapeutic strategy for metastatic cancer.

Keywords: CTC cluster; Methionine adenosyltransferase 2A (MAT2A); PDGFR signaling; PERK; SAM synthesis

DOI: https://doi.org/10.1002/cac2.70072

Front Immunol. 2025 ;16 1626581

Targeting asparagine potentiates anti-PD-L1 immunotherapy in gastric cancer by enhancing CD8+ T cell anti-tumor response.

Mingpai Ge, Longfei Wang, Bowen Zheng, Lu Zhan, Lu Cui, Han Wang, Enyuan Huang, Yuan Xu, Xusheng Chang, Zhaorui Liu, Jun Xu, Kai Yin.

Introduction: Immunotherapy efficacy in gastric cancer (GC) is often constrained by the tumor microenvironment (TME), which is profoundly influenced by aberrant metabolism. Asparagine, an amino acid critical for neoplastic proliferation, also modulates CD8+ T cell metabolic programming. We investigated the impact of targeting asparagine on the GC immune microenvironment and its potential to synergize with anti-PD-L1 therapy.
Methods: The therapeutic efficacy of asparagine targeting was evaluated in GC tumor models. CD8+ T cell populations within the TME were analyzed by flow cytometry, while cytokine and chemokine levels (IFN-γ, GZMB, CXCL9, CXCL10) were quantified by ELISA. The effects on CD8+ T cell activation and antitumor function were assessed in vitro and in vivo. Synergistic efficacy with anti-PD-L1 therapy was evaluated in GC models, and the dependency on CD8+ T cells was confirmed via antibody-mediated depletion experiments.
Results: Targeting asparagine inhibited GC growth in vitro and in vivo, implicating immune system involvement. Mechanistically, asparagine targeting significantly increased the proportion of CD8+ T cells within the TME and upregulated the expression of IFN-γ, GZMB, CXCL9, and CXCL10. Furthermore, combining asparagine targeting with anti-PD-L1 therapy produced synergistic antitumor activity. This combined therapeutic effect was significantly attenuated by the depletion of CD8+ T cells.
Discussion: Our findings indicate that targeting asparagine promotes CD8+ T cell activation and infiltration, thereby remodeling the GC immune microenvironment to enhance host antitumor immunity. The combination of asparagine targeting with anti-PD-L1 therapy elicits potent, synergistic antitumor effects that are demonstrably dependent on CD8+ T cells. This study provides a strong rationale for targeting asparagine metabolism as a novel strategy to improve immunotherapeutic outcomes in GC.

Keywords: CD8 T cell; TME (tumor microenvironment); asparagine; gastric cancer; immunotherapy; metabolism

DOI: https://doi.org/10.3389/fimmu.2025.1626581

Int J Biol Sci. 2025 ;21(14): 6501-6521

Lung Cancer Cell-intrinsic Asparagine Synthetase Potentiates Anti-Tumor Immunity via Modulating Immunogenicity and Facilitating Immune Remodeling in Metastatic Tumor-draining Lymph Nodes.

Ziyu Zhang, Nannan Du, Gege He, Mengting Zhang, Gaifeng Zhang, Jie Gao, Ying Liu, Yuezhen Deng, Lunquan Sun, Min Li.

Background: In non-small cell lung cancer (NSCLC), lymph node (LN) metastasis is a crucial prognostic factor. Asparagine synthetase (ASNS) plays a crucial role in cellular aspartate metabolism and promotes LN metastasis. However, the mechanisms by which LN metastasis affects immune microenvironment remodeling in situ and tumor-draining LNs (TdLNs), as well as the role of ASNS in this process remains unclear. Methods: LN metastatic lung cancer cell lines were established through in vivo selection in a murine model and subsequently analyzed via metabolomic profiling. ASNS expression and its role in modulating immunogenicity were assessed using transcriptomic analysis, western blotting, and immunohistochemistry. Metabolomic profiling, combined with in vitro stimulation assays, identified key metabolic regulators involved in the axis. Furthermore, T-cell kinetics were monitored via flow cytometry, multiplex immunofluorescence and patient datasets. Tissue samples from NSCLC patients with LN metastases following neoadjuvant immunotherapy were employed to validate findings. Results: Elevated aspartate metabolism and ASNS expression were observed in LN metastasis based on metabolomic analyses of LN metastatic lung cancer cell lines and immunohistochemistry of tissue samples from LN metastasis, intrapulmonary implantation, LN injection models and NSCLC patients-derived samples. Higher ASNS expression in LN metastases correlated with enhanced immunogenicity. Mechanically, ASNS promoted the expression of major histocompatibility complex through α-aminobutyric acid auto-secretion in lung cancer cells. Moreover, in vivo and clinical studies revealed that metastatic tumor areas with high ASNS expression facilitated the formation of lymphocyte niches conducive to CD8+T cell activation, memory, and stemness within metastatic TdLNs, particularly in the vicinity of metastatic foci, thus reshaping the immune landscape in both tumors in situ and metastatic LNs. Clinical research confirmed that high ASNS expression in LN metastases correlated with improved efficacy of neoadjuvant immunotherapy in NSCLC patients. Conclusions: ASNS promotes anti-tumor immunity in NSCLC via regulating immunogenicity of cancer cells and immune microenvironment remodeling in metastatic TdLNs. Lung cancer cell-intrinsic ASNS appears to be a promising marker for anti-PD-1-based neoadjuvant immunotherapy.

Keywords: ASNS; NSCLC; lymph node metastasis; neoadjuvant immunotherapy; stem-like T cells

DOI: https://doi.org/10.7150/ijbs.114791

Nat Commun. 2025 Nov 13. 16(1): 9979

A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.

Tianhao Zou, Ran Liu, Gengqiao Wang, Guoliang Wang, Zhengting Jiang, Chuanzheng Wang, Weimin Wang, Mao Cai, Shuhua Zhang, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu.

Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is implicated in various human diseases. However, the mechanisms RIPK1-mediated cell death is regulated by metabolic processes remain unclear. Here, we identify hexokinase 2 (HK2), a critical regulator of glycolysis, as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through its non-metabolic function. HK2 inhibits RIPK1 kinase activity through constitutively phosphorylation at serine 32 of RIPK1. Inhibition of RIPK1 S32-phosphorylation results in RIPK1 kinase activation and subsequent cell death in response to TNFα stimulation. We further show that HK2 is elevated under pathological conditions including liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC) via the transcriptional factor HMGA1. Moreover, the upregulation of HK2 in the liver confers protection against liver IR injury mediated by RIPK1 kinase, while depleting HK2 in HCC cells enhances TNFα-induced cell death and synergistically improves the efficacy of anti-PD1 therapy in an HCC model. Thus, the findings reveal a potential therapeutic avenue for RIPK1-related diseases through manipulating HK2 non-metabolic function.

DOI: https://doi.org/10.1038/s41467-025-64939-1