bims-flamet 2026-01-18 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–01–18
eighteen papers selected by
Peio Azcoaga, Biodonostia HRI

YAP1 Is a Crucial Nexus in the Tumor Microenvironment.
Apoptotic Cancer Cell-Primed Cancer-Associated Fibroblasts Suppress Immunosuppressive Macrophages via WISP-1-Integrin α5β3-STAT1 Signaling in Lung Cancer.
Restoring Antitumor Immunity by Reprogramming Abnormal Lipid Metabolism in the Tumor Microenvironment Using Irisin-Manganese Co-loaded Nanoparticles.
Nerves Stimulates Crosstalk between Gastric Cancer and Group 3 Innate Lymphoid Cells to Enhance Immunosuppression.
Krüppel-Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment.
Intratumoral microbiome: the double-edged sword in remodeling cancer immunotherapy.
Rab37-mediated OPN secretion enriches SPP1+ macrophages through autocrine-paracrine signaling to drive lung tumor progression.
Protein palmitoylation and immune regulation in pancreatic ductal adenocarcinoma: Integrating insights from cross-cancer studies.
Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.
Bacterial Elements Detected in Brain Tumors May Shape Tumor Microenvironment.
Cancer cachexia: molecular basis and therapeutic advances.
Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review).
SLC39A10 drives M2 macrophage polarization and gastric cancer progression through the MAPK14(p38α) pathway.
6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
Decoding the metastatic nexus: how chronic stress reprograms neuroendocrine-metabolic-microbiome circuits to fuel tumor metastasis.
Oxaliplatin-artesunate conjugate intensifies suppression on colorectal cancer by boosting antitumor immunity.
Conditional IL4I1 inactivation triggers tumor-associated macrophage reprogramming and CD8+ T-cell reactivation to control melanoma progression.
VISTA: An Emerging Immune Checkpoint With Clinical Relevance Across Diverse Malignancies.

Curr Med Sci. 2026 Jan 13.

YAP1 Is a Crucial Nexus in the Tumor Microenvironment.

Raghavan Narasimhan, Anshula Narayanasamy, Jaya Padmanabhan, Srikumar Chellappan, Durairaj Mohan Kumar.

  Yes-associated protein-1 (YAP1) is an oncogenic effector of the Hippo signaling pathway, activated in several cancer types, and has been extensively studied in cancer progression and therapy. A large number of studies have established the importance of YAP1 in promoting cell-autonomous functions, including uncontrolled growth, sustained proliferative signaling, drug resistance, and metastasis, across multiple cancer types. Therapeutic targeting of YAP1 to combat incurable neoplasms has been the focus of intense investigations. Solid tumors exhibit an organ-like morphology that comprises malignant cells, nonmalignant cells such as fibroblasts, endothelial cells, and immune cells, and non-cellular components, including the extracellular matrix and exosomal vesicles. Tumor progression is accompanied by persistent, reciprocal interactions between malignant cells and other cell types in the tumor microenvironment (TME). Ample evidence indicates the functional importance of YAP1 in nonmalignant components of the TME, which fuel cancer progression. In this review, we provide a comprehensive overview of the functional significance of YAP1 and its downstream signaling pathways across different compartments of the TME, which orchestrate cancer growth, stemness, drug resistance, and metastasis. In particular, this review focuses on understanding the mechanisms by which YAP1 drives distinct cell types in the TME, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and exosome-derived factors, to fuel tumor progression. Furthermore, we summarize the progress in the development of recent YAP1 inhibitors, their mechanisms of action in Hippo-YAP1-dependent cancers, and their combination benefits with existing treatment strategies.

Keywords:   TEAD; Tumor angiogenesis; Cancer stem cells; Cancer-associated fibroblasts; Exosomes; Hippo signaling pathway; Tumor microenvironment; Tumor stroma; Tumor-associated macrophages; Yes-associated protein 1

DOI:  https://doi.org/10.1007/s11596-025-00151-y
Int J Biol Sci. 2026 ;22(2): 995-1015

Apoptotic Cancer Cell-Primed Cancer-Associated Fibroblasts Suppress Immunosuppressive Macrophages via WISP-1-Integrin α5β3-STAT1 Signaling in Lung Cancer.

Kyungwon Yang, Kiyoon Kim, Hee Ja Kim, Jeesoo Chae, Ye-Ji Lee, Shinyoung Kim, Young-Ho Ahn, Jihee Lee Kang.

  Cell death within the tumor microenvironment (TME) plays a pivotal role in shaping tumor-specific immunity. The dynamic interplay between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) is central to tumor progression and immune regulation. Here, we show that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells selectively impairs the survival of M2-like macrophages, induces apoptosis, and promotes their reprogramming toward an M1-like phenotype. These effects were abrogated by knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs, identifying WISP-1 as a key paracrine effector. Mechanistically, WISP-1 signals through the integrin α5β3-STAT1 axis to mediate M2 TAM apoptosis and M1-like reprogramming. In vivo, intratumoral injection of CM derived from CAF exposed to apoptotic 344SQ cells reduced overall TAM density, decreased the proportion of M2-like TAMs, and promoted their reprogramming toward an M1-like phenotype, accompanied by STAT1 activation in M2 TAMs. This phenotypic shift was associated with increased infiltration of cytotoxic CD8+ T cells and reduced accumulation of regulatory T cells within the tumor. Notably, these effects were abolished by either depletion of WISP-1 from the CM or pharmacological inhibition of STAT1 following recombinant WISP-1 administration. Collectively, our findings identify the WISP-1-integrin α5β3-STAT1 axis as a novel therapeutic target for TAM reprogramming and tumor suppression in lung cancer.

Keywords:  CAFs; Integrin α5β3; STAT1; TAMs; WISP-1; apoptotic cancer cells

DOI:  https://doi.org/10.7150/ijbs.124282
Acta Biomater. 2026 Jan 08. pii: S1742-7061(26)00021-8. [Epub ahead of print]

Restoring Antitumor Immunity by Reprogramming Abnormal Lipid Metabolism in the Tumor Microenvironment Using Irisin-Manganese Co-loaded Nanoparticles.

Xingzhe Tang, Yufei Zhao, Yan Gu, Min Chen, Jingyue Dai, Yang Jiang, Yuqing Lan, Ying Cui, Lin Fu, Xinxiang Li, Hui Mao, Zhaogang Teng, Xin-Gui Peng.

  Targeting dysregulated lipid metabolism within the tumor microenvironment (TME) has emerged as a promising strategy for restoring anti-tumor immunity and reversing immune suppression to improve therapeutic efficiency. This study reports a nanomaterial platform for co-delivery of irisin and manganese ions (Mn²⁺) to exert cumulative effects of modulating lipid metabolism dysregulation and ameliorating the immunosuppressive TME in triple-negative breast cancer (TNBC). Irisin stimulates lipolysis and inhibits lipogenesis, whereas Mn²⁺ strengthen irisin binding to integrin αVβ5 over-expressed in various cancers. Developed manganese-containing mesoporous organosilica nanoparticles (MMONs) loaded with irisin (MMONs-irisin) were stable in physiological conditions but enabled pH responsive release of irisin and glutathione (GSH) responsive release of Mn²⁺ within the TME in a murine model of TNBC. Together, irisin and Mn2+ effectively reduced intracellular lipid droplets (LDs) across different cell types in vitro as well as intratumoral LDs in TME, thereby reprogramming dysregulated lipid metabolism and subsequently enhancing the antigen presentation in dendritic cells (DCs) and antigen-specific cytotoxicity of CD8⁺ T cells. Concomitantly, MMONs-irisin significantly increased immunogenicity of TNBC, involving activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway following depletion of LDs. Together, MMONs-irisin effectively delivers a coordinated cascade of immune-potentiating effects to disrupt immunosuppressive TME and restore anti-tumoral immunity, significantly improving the treatment responses of anti-programmed cell death protein 1 (aPD-1). STATEMENT OF SIGNIFICANCE: Dysregulated lipid metabolism in the tumor microenvironment suppresses antitumor immunity. However, existing lipid-targeting strategies remain confined to specific cell types and are limited by systemic toxicity. To address this challenge, we developed irisin-manganese co-loaded nanoparticles that reprogram abnormal lipid metabolism in triple-negative breast cancer. This intervention restores tumor cell immunogenicity, dendritic cell antigen presentation, and CD8⁺ T cell cytotoxicity, thereby augmenting antitumor immune responses and potentiating the efficacy of anti-PD-1 therapy. These findings underscore a biomaterial-based strategy to overcome metabolic immune suppression and enhance cancer immunotherapy.

Keywords:  Breast cancer; Immunotherapy; Irisin-manganese co-loaded nanoparticles; Lipid metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.actbio.2026.01.011
Cancer Res. 2026 Jan 14.

Nerves Stimulates Crosstalk between Gastric Cancer and Group 3 Innate Lymphoid Cells to Enhance Immunosuppression.

Fangli Liao, Yanran Tong, Hua Sun, Sen Chen, Siyang Wen, Yan-E Du, Linshan Jiang, Tong Huang, Manran Liu, Weixian Chen, Liping Yang.

The immunosuppressive tumor microenvironment (TME) enables cancer cells to evade clinical immunotherapies. Neural networks are vital components of the TME, and interactions between cancer cells, neuronal cells, and immune cells mediate immunosuppression. Hence, understanding the mechanisms of intercellular crosstalk could inform immunomodulatory approaches to enhance immunotherapy efficacy. Here, we found that the vagus nerve regulated the crosstalk between gastric cancer (GC) cells and group 3 innate lymphoid cells (ILC3s), boosting immune resistance in GC by enhancing programmed death ligand 1 (PD-L1) expression. Specifically, the infiltrated vagus nerve released acetylcholine (ACh) that elevated the expression of lipase ABHD16A in GC cells, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the TME. LysoPS facilitated the proliferation and activation of ILC3s in TME, resulting in production of the cytokine interleukin (IL)-22 via the GPR34/AKT/STAT3 axis. In turn, IL-22 triggered the unfolded protein response (UPR) in GC cells, which led to an increase in PD-L1 expression that enhanced immune resistance. Importantly, targeting ACh or the crosstalk between GC cells and ILC3s significantly enhanced the efficacy of anti-PD-L1 immunotherapy. Serum levels of LysoPS and IL-22 were elevated in GC patients, particularly those with perineural invasion. Collectively, these findings provide valuable insights into the crosstalk between GC cells, nerve cells, and ILC3s that regulates immunosuppression and response to ant-PD-L1 immunotherapy, emphasizing the potential clinical significance of this axis for detecting and treating GC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3092
Cancer Med. 2026 Jan;15(1): e71498

Krüppel-Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment.

Min Tang, Binle Tian, Jingyi Zhou, Di Ma, Rongze Sun, Qi Li.

   OBJECTIVE: Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays context-dependent roles in cancer. It functions as either a tumor suppressor or an oncogene depending on tumor type and cellular context. This review aimed to comprehensively summarize the roles of KLF4 in the tumor microenvironment (TME) and evaluate its potential as a therapeutic target.
METHODS: We conducted a comprehensive literature review to elucidate the expression patterns, regulatory mechanisms, and functional roles of KLF4 across different TME components, including cancer cells, immune cells, cancer-associated fibroblasts, pericytes, and extracellular matrix.
RESULTS: KLF4 exhibits dual roles in cancer cells, acting as a tumor suppressor in gastric, lung, and pancreatic cancers while promoting oncogenesis in breast, colorectal, and prostate cancers. In the TME, KLF4 regulates macrophage polarization (M1/M2), T-cell exhaustion, NK cell activity, and MDSC recruitment. Additionally, KLF4 modulates CAF activation and ECM remodeling. KLF4 expression is regulated by miRNAs, lncRNAs, and epigenetic modifications. Emerging therapeutic strategies targeting KLF4, such as APTO-253, show promise in preclinical and early clinical trials.
CONCLUSIONS: KLF4 serves as a hub gate orchestrating cell crosstalk within the TME. Understanding its context-dependent functions may facilitate the development of KLF4-targeted therapies for precision oncology.

Keywords:  KLF4; cancer; immune cells; tumor microenvironment

DOI:  https://doi.org/10.1002/cam4.71498
Mol Cancer. 2026 Jan 13.

Intratumoral microbiome: the double-edged sword in remodeling cancer immunotherapy.

Di Yan, Ying Yu, Chengtong Liang, Zixing Cui, Lei Shi, Guiling Li, Chuanli Ren.

  Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8+ T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.

Keywords:  Cancer immunotherapy; Intratumoral microbiome; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02566-6
Oncogenesis. 2026 Jan 14.

Rab37-mediated OPN secretion enriches SPP1+ macrophages through autocrine-paracrine signaling to drive lung tumor progression.

You-En Yang, Yu-An Lin, Lun-Ling Ling, I-Ying Kuo, Wan-Ting Kuo, Hsuan Liu, Yi-Ching Wang.

Tumor-associated Macrophages (TAMs) are highly plastic immune cells that shape the tumor microenvironment (TME) and influence cancer progression. However, the molecular determinants governing their functional heterogeneity remain incompletely understood. In this study, we identify Rab37 as a key regulator that remodels the states of macrophages within the lung TME. Single-cell RNA sequencing revealed that Rab37 wild-type (WT) tumors were enriched in immunosuppressive Spp1+ TAMs, whereas Rab37 knockout (KO) tumors contained a higher proportion of Thbs1+ TAMs, suggesting Rab37-dependent shifts in macrophage programming. Mechanistically, Rab37 promoted osteopontin (OPN) secretion, which activated STAT3 signaling to establish an autocrine feedback loop that sustained Spp1 expression and induced M2-like polarization. Paracrine OPN signaling further enhanced lung cancer cell proliferation, migration, and invasion. In clinical lung cancer specimens, CD163+/Rab37+/OPN+ TAMs correlated with recurrence and poor survival, and multivariate analysis confirmed their independent prognostic value. Together, these findings demonstrate that Rab37 governs macrophage phenotype and function by orchestrating OPN/STAT3 signaling, thereby reinforcing an immunosuppressive TME and promoting lung cancer progression. Targeting the Rab37-OPN axis may thus represent a promising therapeutic strategy.

DOI: https://doi.org/10.1038/s41389-026-00596-3
Biochim Biophys Acta Rev Cancer. 2026 Jan 14. pii: S0304-419X(26)00004-1. [Epub ahead of print] 189532

Protein palmitoylation and immune regulation in pancreatic ductal adenocarcinoma: Integrating insights from cross-cancer studies.

Xiaotong Cui, Changlei Li, Xue Zhong, Ao Sun, Yingying Lan, Zusen Wang.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunologically "cold" tumor microenvironment (TME), marked by a dense stromal barrier, impaired antigen presentation, and extensive infiltration of immunosuppressive cells. In recent years, protein S-palmitoylation, a reversible lipid modification, has emerged as a critical mechanism regulating immune signaling, receptor trafficking, and membrane localization of immune-related proteins. This review highlights the multifaceted roles of S-palmitoylation in shaping the immunological landscape of PDAC. We systematically discuss its involvement in immune checkpoint regulation, T-cell activation, antigen presentation, and the function of myeloid-derived suppressor cells (MDSCs), integrating evidence from both PDAC and other cancer types. Special attention is given to key palmitoylated molecules, including programmed death-ligand 1 (PD-L1), cluster of differentiation 80 (CD80), lymphocyte-specific protein tyrosine kinase (LCK), linker for activation of T cells (LAT), interferon-induced transmembrane proteins (IFITMs), and major histocompatibility complex class I (MHC-I), and their potential roles in the immunosuppressive network of PDAC. Moreover, we explore therapeutic strategies targeting palmitoylation, such as the use of selective palmitoyltransferase inhibitors, the design of palmitoylation-deficient CAR-T cells, and the development of nanotechnology-based delivery platforms. By incorporating cross-cancer insights, we propose that palmitoylation is a promising regulatory axis for reprogramming the PDAC immune microenvironment and overcoming resistance to immunotherapy.

Keywords:  Immune checkpoint; Immune evasion; Nanomedicine; Palmitoylation; Pancreatic ductal adenocarcinoma; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189532
Adv Sci (Weinh). 2026 Jan 12. e15403

Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.

Jiajing Gong, Yuhang Xie, Zhijie Weng, Yongzhi Wu, Longjiang Li, Bo Li.

  Lactate has evolved from being regarded as a byproduct of glycolysis to a pivotal regulator of cancer metabolism and signaling. The Warburg effect underscores how elevated lactate production meets the biosynthetic demands of highly proliferative cancer cells, while shaping an immunosuppressive tumor microenvironment (TME) that supports cancer growth and metastasis. The discovery of lactylation, a novel post-translational modification, has further expanded the conceptual landscape, revealing how lactate serves as both a metabolite and a signaling molecule that couples metabolic reprogramming with gene regulation. This review delineates how lactate dynamically shuttles through the TME and boosts cancer malignancy, including proliferation, metastasis, drug resistance, and immune evasion. Also, this review integrates and discusses how lactate-driven lactylation bridges metabolic and epigenetic control. Furthermore, emerging therapeutic strategies targeting lactate metabolism and lactylation are summarized, revealing their promise in cancer immunotherapy. Collectively, a comprehensive perspective is provided on the multifaceted roles of lactate and lactylation in cancer biology and, more importantly, highlights potential translational avenues for clinical applications.

Keywords:  cancer; lactate; lactylation; metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.1002/advs.202515403
Cancer Discov. 2026 Jan 07. OF1

Bacterial Elements Detected in Brain Tumors May Shape Tumor Microenvironment.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-001
Signal Transduct Target Ther. 2026 Jan 13. 11(1): 16

Cancer cachexia: molecular basis and therapeutic advances.

Yuting Tan, Rui Xue, Yuwei Pan, Zongsheng He, Xiao Hu, Yaping Li, Ke Li, Xuan Zhang, Xiu-Wu Bian, Bin Wang.

The dynamic interplay between neoplastic cells and the host has been increasingly recognized as important players in the pathogenesis of cancer cachexia, a syndrome affecting ~50-80% of cancer patients with various incidences of different types of malignancies. Despite its prevalence, a comprehensive understanding of cancer cachexia progression, with a holistic view at the cross-organismal, cellular and molecular levels, remains elusive. In this review, we undertake an in-depth exploration of the relevant target organs and their regulatory roles in cancer cachexia, with a particular focus on macroenvironmental interactions via various organismal crosstalk axes. Moreover, we highlight how systemic metabolic remodeling, a hallmark of cancer cachexia, plays essential roles in modulating the inflammatory responses of immune and stromal cells in the tumor microenvironment (TME). These cellular responses, in turn, disrupt energy metabolism in distant organs and perturb organismal homeostasis by secreting a variety of mediators that activate specific signaling pathways, thereby fostering a vicious cycle that exacerbates cancer cachexia. We comprehensively summarize these complex cellular and molecular networks that constitute reciprocally regulatory dynamics between systemic metabolic reprogramming and inflammatory cascades. Notably, targeting the multifaceted interplay of organismal metabolic remodeling and cancer-associated inflammation holds great promise for clinical translation, as illustrated by a series of innovative therapeutic strategies and ongoing clinical trials aimed at mitigating cachexia in cancer patients.

DOI: https://doi.org/10.1038/s41392-025-02331-7
Int J Oncol. 2026 Mar;pii: 32. [Epub ahead of print]68(3):

Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review).

Chaoqun Li, Chenge Qin, Xingchen Li, Jinzhu Wang, Yang Li, Qin Sun.

 Hypoxic tumor microenvironment (TME) is a common occurrence in the development of solid tumors, which activates hypoxia‑inducible factors (HIFs) and their downstream signaling pathways in cancer cells to facilitate tumor progression and immune escape. However, among the various immune cells that constitute innate and adaptive immune systems, HIFs have a more intricate function; moreover, different isoforms of HIFs play different functions under spatial and temporal conditions. HIFs are conducive to the adaptation of various immune cells to the hypoxic TME. The stability of HIF‑α can regulate metabolism and directly regulate the expression of immune genes. Additionally, the activation of HIF signaling may also inhibit the development of immune cells in some tumor environments, affecting the antigen recognition and killing processes to assist cancer cells in immune escape. Therefore, understanding the relationship between HIF signaling and immune cells more comprehensively may yield substantial benefits for the immunotherapy of various types of cancer. The present study reviewed the role of HIFs in immunity, including their role in T cells, B cells, macrophages, neutrophils, dendritic cells and natural killer cells. It also discussed the effectiveness of HIF targeted therapy in clinical application, the challenges associated with it and the development of a precise targeting drug delivery system. The present review may help researchers comprehend the tumor immune process in a hypoxic microenvironment. It aimed to offer novel strategies for cancer immunotherapy and prolonging the overall survival of patients..

Keywords: hypoxia‑inducible factor; immune cells; tumor immunity; tumor immune escape; tumor microenvironment

DOI: https://doi.org/10.3892/ijo.2026.5845
iScience. 2026 Jan 16. 29(1): 114400

SLC39A10 drives M2 macrophage polarization and gastric cancer progression through the MAPK14(p38α) pathway.

Yinhua Liang, Mengting Li, Chihao Zhang, Chunpeng Pan, Shoulian Wang, Xin Xu, Jiwei Yu.

  The zinc transporter SLC39A10 serves as a risk factor for malignant progression in gastric cancer (GC), characterized by the formation of an immunosuppressive tumor microenvironment (TME). As key cellular components within this microenvironment, both malignant cells and macrophages are influenced by SLC39A10, yet its regulatory mechanisms at the subpopulation level remain unclear. Using single-cell RNA sequencing and functional experiments, we investigated the cell-type-specific role of SLC39A10 in GC. Results demonstrated that oeSLC39A10 tumor cells exhibit activated MAPK14 signaling pathway, while tumor-associated macrophages (TAMs) display a biased M2 polarization state. These two cell populations establish intercellular communication through secretory factors IL-10 and TGF-β, synergistically promoting tumor proliferation and angiogenesis. This study identifies an SLC39A10-MAPK14-M2 macrophage regulatory axis that critically influences immune microenvironment remodeling and GC progression. Targeting this signaling axis may provide a viable therapeutic approach to alter the TME and suppress disease advancement.

Keywords:  Cancer; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.114400
Nat Commun. 2026 Jan 14. 17(1): 229

6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.

Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.

The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-025-68102-8
Am J Cancer Res. 2025 ;15(12): 5058-5083

Decoding the metastatic nexus: how chronic stress reprograms neuroendocrine-metabolic-microbiome circuits to fuel tumor metastasis.

Yuxin Wang, Wenchen Sun, Haitao Li, Fei Xu, Wenqiang Cui.

  Metastasis, the leading cause of death in patients with solid tumors, involves the spread of cancer cells to distant organs. While genetic and environmental factors contribute, chronic stress is a crucial factor in metastatic progression by disrupting neuroendocrine, immune, metabolic, and microbial homeostasis. This review synthesizes evidence linking chronic stress to tumor metastasis through three pathways: (1) direct effects on tumor cell metabolism, (2) remodeling of the tumor microenvironment, and (3) dysregulation of the gut microbiota. Describe how activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system influence epithelial-mesenchymal transition, immune evasion, and angiogenesis via β-adrenergic and glucocorticoid receptor signaling. Explore how microbial metabolites and barrier dysfunction influence immune and neuroendocrine circuits, creating a pro-metastatic loop. Finally, we highlight therapeutic strategies, including psychological interventions and pharmacologic approaches, to alleviate chronic stress. This review proposes a mechanistic framework linking neuroendocrine signaling, metabolic reprogramming, and the microbiome-immune axis.

Keywords:  Chronic stress; gut microbiota; metabolic reprogramming; neuroendocrine regulation; tumor metastasis; tumor microenvironment

DOI:  https://doi.org/10.62347/OKKH6279
J Inorg Biochem. 2026 Jan 03. pii: S0162-0134(26)00001-2. [Epub ahead of print]277 113212

Oxaliplatin-artesunate conjugate intensifies suppression on colorectal cancer by boosting antitumor immunity.

Yehong Tan, Tao Yang, Siran Jiang, Shumeng Li, Linxiang Cai, Ying Wang, Zijian Guo, Xiaoyong Wang.

  Immunosuppressive tumor microenvironment is the major obstacle for antitumor immunotherapy. Elimination of myeloid-derived suppressor cells (MDSCs) potentiates immunotherapy for various solid tumors. Oxaliplatin-artesunate complex OPA decreases MDSCs by inhibiting CD33 and the triggering receptor expressed on myeloid cells 2 (TREM2) in the TME, and enhancing dendritic cell maturation due to its ability to facilitate immunogenic cell death and activate the cyclic-GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Moreover, OPA upregulates the costimulatory molecule CD28 and downregulates the immune checkpoint cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells, thus impeding the T cell depletion and immunosuppression. The activation of immune circulation and immunosignal pathway increases the chemotherapeutic activity of parent oxaliplatin. In addition, OPA serves as a cancer vaccine to inhibit tumor metastasis and reoccurrence. Lastly, the stability and safety profiles are superior to that of oxaliplatin. OPA is a unique chemoimmunotherapeutic agent with a distinct mechanism of action and prominent efficacy on orthotopic colorectal cancer in mouse models.

Keywords:  Anticancer drug; Cancer vaccine; Chemoimmunotherapy; Colorectal cancer; Immunosuppression; Platinum complex

DOI:  https://doi.org/10.1016/j.jinorgbio.2026.113212
Cancer Immunol Res. 2026 Jan 15.

Conditional IL4I1 inactivation triggers tumor-associated macrophage reprogramming and CD8+ T-cell reactivation to control melanoma progression.

Malvina Seradj, Saniya Kari, Anna Llebaria-Fabrias, Adrien Rouault, Arthur Herrmann, Renée Lengagne, Masashi Kato, Flavia Castellano, Valérie Molinier-Frenkel, Amadeu Llebaria, Nadège Bercovici, Armelle Prévost-Blondel.

Tumor-associated macrophages (TAMs) represent the main immune population infiltrating cancers, and their abundance is generally correlated with a poor prognosis. The acquisition of protumor properties by TAMs involves several mechanisms, including expression of immunosuppressive enzymes. In this study, we explored the role of the enzyme IL-4 induced gene 1 (IL4I1) expressed by TAMs in murine models of melanoma. We found that IL4I1 expression was increased in subsets of TAMs during spontaneous melanoma progression and this increase could be blocked by TNF-α, IL-12, and IL-1β co-neutralization. Macrophage-specific IL4I1 deletion delayed tumor onset and metastatic dissemination. Mechanistically, targeting IL4I1 restored antitumor functions of TAMs with increased antigen-presenting capacity and restored the proliferative and cytotoxic capacities of CD8+ T cells. Chemical blockade of IL4I1 partially reproduced these results. Overall, we demonstrate the key role of IL4I1 in TAM-mediated immune escape of melanoma. As most human tumors contain TAMs expressing IL4I1, our results may have implications for cancer immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-1159
Immune Netw. 2025 Dec;25(6): e44

VISTA: An Emerging Immune Checkpoint With Clinical Relevance Across Diverse Malignancies.

Hiba Laraki, Ibtissam Rezouki, Khalil Choukri, Abdallah Badou.

  Immune checkpoint inhibitors (ICIs) offer tremendous promise as therapeutic targets for a range of tumor types, and their development is advancing rapidly in cancer treatment. Nevertheless, the limited efficacy of anti-PD-1/PD-L1 immunotherapy in several cancers has driven researchers to explore other immune checkpoints as potential therapeutic targets. The inhibitory V-domain Ig suppressor of T-cell activation (VISTA) appears to be a captivating candidate. As a member of the B7 family, VISTA is expressed on hematopoietic cells and has the ability to significantly suppress T cell function and the anti-tumor immune response. In this review, our objective is to shed light on the multifaceted potential of VISTA as a therapeutic target. We will highlight the expressions and role of VISTA in various cancer types. Subsequently, we will go through distinct potential VISTA ligands, while underscoring the role of the pathway within the tumor microenvironments (TME). Finally, we will conclude with a comprehensive overview of the latest clinical trials, highlighting VISTA's emerging potential in cancer treatment.

Keywords:   Immune checkpoint inhibitors; Clinical trial; Tumor microenvironment; VSIR protein, human

DOI:  https://doi.org/10.4110/in.2025.25.e44