bims-flamet 2026-01-04 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–01–04
23 papers selected by
Peio Azcoaga, Biodonostia HRI

Remodeling the tumor microenvironment: regulatory effects of β-sitosterol and luteolin on the immunosuppressive milieu in endometrial carcinoma and implications for combinatorial immunotherapy.
Editorial: Metabolic crosstalk between cancer cells and immune cells in the tumor microenvironment: cellular and molecular insights, and their therapeutic implications.
Tumor associated macrophages in gastric cancer dual roles in immune evasion and clinical implications for targeted therapy.
Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment.
High potassium enhances the immunosuppressive function of myeloid-derived suppressor cells via Kir4.1-dependent metabolic reprogramming and promotes tumor immune escape.
Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.
Proteoglycans in Prostate Cancer Progression and Therapy Resistance.
Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.
CD147 at the crossroads of glycoprotein networks, metabolic reprogramming, and metastatic progression.
A new strategy for CAR-T therapy in solid tumors: IL-15-autocrine signaling augments tumor stroma depletion and promotes a TSCM subset in the TME.
Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
The role of depression in the progression of tumor cell inflammation and the potential regulatory mechanisms of aerobic exercise: a narrative review from molecular and cellular perspectives.
Chimeric antigen receptor dendritic cells suppress melanoma growth in preclinical cancer models.
Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.
Deciphering the Role of Mast Cells in HPV-Related Cancers.
Non-Glycosylated, Legumain-Cleavable ISACs Drive Potent Anti-Tumor Immunotherapy via a Bystander Effect.
Mechanical microenvironment and its role in hepatocellular carcinoma oncogenesis and progression.
Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
PH20-modified exosomes loaded curcumin inhibit desmoplastic breast cancer by breaking extracellular matrix barrier and normalizing cancer-associated fibroblasts.
Advances in the clinical application of bispecific antibodies in cancer therapy.
Tryptophan metabolism in tumor microenvironment and therapeutic Implications.
Extracellular vesicles in tumor microenvironment modulation and clinical diagnosis.
Targeting glioma-associated microglia and macrophages: a new frontier in glioblastoma immunotherapy.

Front Immunol. 2025 ;16 1669606

Remodeling the tumor microenvironment: regulatory effects of β-sitosterol and luteolin on the immunosuppressive milieu in endometrial carcinoma and implications for combinatorial immunotherapy.

Guojie Ji, Pengbo Wang, Zhihong Kong, Xiangxiang Cao, Xiaowei Shi, Huigen Feng, Huanhuan Hu.

  Endometrial carcinoma (EC), particularly high-risk molecular subtypes like p53abn and NSMP, is frequently characterized by a tumor immunosuppressive tumor microenvironment (TME) that drives progression, metastasis, and resistance to therapy. This immunosuppressive milieu is orchestrated by key cellular components, including M2-polarized tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), PD-L1-expressing tumor cells, and pro-fibrotic cancer-associated fibroblasts (CAFs), which collectively inhibit effector T cell function and promote immune exclusion/desert phenotypes. Natural products offer promising multi-targeted strategies to remodel the TME. This review comprehensively summarizes the potent immunomodulatory effects of the phytosterol β-sitosterol (BSS) and the flavonoid luteolin (Lut) specifically within the EC TME. We detail how BSS and Lut synergistically reprogram TAMs towards an M1 phenotype, inhibit Treg differentiation/function and MDSC expansion, enhance CD8+ T cell recruitment, activation, and cytotoxicity (e.g., by downregulating PD-1/TIM-3), and suppress CAF-mediated immunosuppression and fibrosis. Mechanistically, these effects are achieved through targeting critical signaling pathways (STAT3, NF-κB, PI3K/AKT, Wnt/β-catenin) and modulating key chemokines/cytokines (e.g., reducing TGF-β, IL-10, CXCL12; increasing CXCL9/10, IFN-γ). Critically, BSS and Lut demonstrate significant potential to overcome resistance to immune checkpoint inhibitors (ICIs), particularly in immune-cold EC subtypes. By remodeling the immunosuppressive TME, BSS/Lut combinations can enhance ICI efficacy, as evidenced by preclinical data showing increased tumor suppression rates and T cell infiltration. While challenges remain, including EC-specific validation, bioavailability optimization, and molecular subtype stratification, BSS and Lut represent promising natural adjuvants for combinatorial immunotherapy, offering novel strategies to improve outcomes for patients with aggressive or treatment-refractory EC.

Keywords:  endometrial carcinoma; flavonoid luteolin; phytosterol β-sitosterol; tumor immunosuppressive microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1669606
Front Oncol. 2025 ;15 1751044

Editorial: Metabolic crosstalk between cancer cells and immune cells in the tumor microenvironment: cellular and molecular insights, and their therapeutic implications.

Parmanand Malvi, Shivendra Vikram Singh, Balkrishna Chaube.



Keywords:  cancer immunotherapy; cancer metabolism; immune response; immune-cell metabolism; metabolic reprogramming; therapeutic target; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1751044
Front Immunol. 2025 ;16 1706744

Tumor associated macrophages in gastric cancer dual roles in immune evasion and clinical implications for targeted therapy.

Chang Wang, Xu Fan, Xiaomen Sun, Yi Xu, Yanna Sun, Jidong Liu.

  Gastric cancer (GC) remains a major global health burden with persistently high mortality despite therapeutic advances. Accumulating evidence highlights the pivotal role of tumor-associated macrophages (TAMs) in orchestrating gastric tumor progression through immune suppression, angiogenesis, extracellular matrix remodeling, and metastasis. Within the tumor microenvironment (TME), TAMs exhibit functional plasticity, often polarizing toward an M2-like phenotype that promotes immunosuppression and tumorigenicity. These cells actively participate in immune evasion via immune checkpoint expression and cytokine-mediated T cell inhibition, while also facilitating lymphovascular invasion and chemoresistance through exosome-mediated crosstalk. The density and phenotype of TAMs have been associated with prognosis and therapeutic response in GC. Recent studies have proposed TAMs as promising targets for therapy, with strategies focusing on depleting M2 subsets, reprogramming toward M1 phenotypes, and blocking TAM-driven oncogenic signaling. Targeted interventions, including MENK, paclitaxel, and NF-κB inhibitors, have shown potential in preclinical models. This review comprehensively discusses the mechanistic roles of TAMs in GC and evaluates emerging TAM-targeted therapeutic strategies that may enhance the efficacy of immunotherapy and improve patient outcomes.

Keywords:  gastric cancer; immune evasion; immunotherapies; prognosis; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1706744
World J Clin Oncol. 2025 Dec 24. 16(12): 111086

Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment.

Thangavelu Shalini, Ganapasam Sudhandiran.

  Fibrosis is marked by the excessive accumulation of extracellular matrix (ECM) components, leading to tissue scarring and progressive loss of organ function. Myofibroblasts, which emerge during tissue repair, are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells. Their expression of α-smooth muscle actin facilitates contractile activity, while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression. Beyond ECM production, myofibroblasts play a significant role in the tumor microenvironment (TME) of various solid tumors. The TME is a complex network of immune cells, blood vessels, ECM components, and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells, thereby influencing tumor growth, progression, and therapy responsiveness. Through these interactions, myofibroblasts modulate inflammation, angiogenesis, and tissue remodeling. Maintaining myofibroblast homeostasis is therefore crucial, as its disruption can drive the onset of chronic fibrotic conditions and malignancies. This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models, including hypertrophic scar, idiopathic pulmonary fibrosis, oral submucous fibrosis, cardiac fibrosis, and the desmoplastic stroma of pancreatic and breast cancers.

Keywords:  Cancer-associated fibroblasts; Extracellular matrix remodeling; Fibroblast activation; Fibrosis resolution; Mechanotransduction in fibrosis; Myofibroblast apoptosis; Tumor microenvironment

DOI:  https://doi.org/10.5306/wjco.v16.i12.111086
Int J Cancer. 2025 Dec 29.

High potassium enhances the immunosuppressive function of myeloid-derived suppressor cells via Kir4.1-dependent metabolic reprogramming and promotes tumor immune escape.

Zhiqi Xie, Jiayi Liu, Ying Chen, Kexin Wang, Ziyi Hong, Yanjie Li, Luqiong Liang, Jinglu Bi, Yuanzhen Jin, Weida Shen, Masashi Tachibana, Zeren Shen, Jinjin Shao.

  Despite advances in cancer immunotherapy, low response rates remain a critical clinical challenge. Myeloid-derived suppressor cells (MDSCs) drive tumor immune evasion by directly suppressing antitumor immunity, positioning them as prime therapeutic targets to improve immunotherapy efficacy. While dysregulated ionic microenvironments, particularly elevated potassium, are emerging as broad-spectrum immunomodulators, the role of high potassium in regulating MDSC function remains poorly understood. Here, we demonstrate that elevated extracellular potassium reprograms MDSC differentiation toward an immunosuppressive phenotype via the activation of the inwardly rectifying potassium channel Kir4.1. Mechanistically, Kir4.1 triggers metabolic rewiring by upregulating fatty acid-binding protein 3, thereby enhancing fatty acid uptake and oxidation to fuel the production of immunosuppressive molecules. In preclinical models, pharmacological inhibition of Kir4.1 with VU0134992 reversed MDSC-mediated T cell suppression, remodeled the tumor microenvironment, and synergized with anti-PD-1 therapy to achieve superior antitumor responses. Clinically, elevated Kir4.1 expression in tumor-infiltrating MDSCs correlates with an adverse prognosis in patients with lung and gastric cancer. Our study establishes Kir4.1 as a critical metabolic regulator governing MDSC functionality and proposes targeting potassium signaling as a strategy to overcome resistance to cancer immunotherapies.

Keywords:  Kir4.1; high potassium; immunotherapy; metabolic; myeloid‐derived suppressor cells

DOI:  https://doi.org/10.1002/ijc.70313
Pharmaceutics. 2025 Nov 26. pii: 1520. [Epub ahead of print]17(12):

Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.

Alex Wade Song, Xiaotong Song.

  Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments.

Keywords:  CAR T cells; adenosine; hypoxia; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics17121520
Medicina (Kaunas). 2025 Nov 27. pii: 2112. [Epub ahead of print]61(12):

Proteoglycans in Prostate Cancer Progression and Therapy Resistance.

Ivana Samaržija.

  The extracellular matrix (ECM) is a complex noncellular network of (macro-)molecules that surrounds and supports diverse cells in tissues and organs. In cancer, ECM is a part of the tumor microenvironment (TME) that embeds its cellular components including cancer cells and the neighboring non-cancerous stromal cells such as fibroblasts, endothelial, and immune cells. Given the complexity of players and interactions that the ECM participates in and is exposed to in the TME, it does not come as a surprise that many of the processes that drive cancer progression take part precisely in the ECM compartment of the TME. Along with diverse glycoproteins and collagens, proteoglycans (PGs) are among the main components of the core ECM. PGs are composed of a protein core to which glycosaminoglycan chains are attached. Considering the structural diversity of these molecules and their 'hybrid' nature, it is not surprising that they are involved in a variety of processes that are vital for surrounding cells. Moreover, they are secreted by both cancer and stromal cells, contributing to the complexity of interactions in the TME. In prostate cancer, PGs have been shown to be involved in many steps of its progression; the most prominent examples include the seemingly tumor-promoting roles of versican, perlecan, and biglycan, and the tumor-suppressive roles of decorin and betaglycan. The role of syndecan 1 is a bit more complex; namely, the nature of its role is context dependent. In this narrative review article, the roles of PGs in prostate cancer progression and therapy resistance are discussed in more detail.

Keywords:  biomarker; cancer progression; extracellular matrix; prostate cancer; proteoglycan; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/medicina61122112
J Control Release. 2025 Dec 30. pii: S0168-3659(25)01201-5. [Epub ahead of print] 114587

Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.

Yanjun Liu, Dongqi Sun, Wenshi Li, Zhixiao Zhang, Ce Li, Xiaofang Che, Shenwu Zhang.

  Immunotherapy has emerged as a transformative approach in cancer treatment. However, its efficacy remains limited in many cases. A key factor contributing to this limitation is metabolic reprogramming within the tumor microenvironment (TME), which suppresses immune cell function and promotes tumor progression. Recently, nanotechnology-based approaches have opened new ways to modulate tumor metabolism and enhance immunotherapy. This review outlines nanoscale strategies aimed at reprogramming tumor metabolism to potentiate antitumor immunity. We begin by discussing the rational design of immune-metabolic nanoregulators, along with key immunometabolic pathways and their regulatory mechanisms. Next, nanotechnology strategies for targeted metabolic intervention at the cellular and microbial levels, as well as the metabolic characteristics of TME are systematically summarized. Furthermore, we highlight recent advances in nanomedicine-based metabolic regulators and evaluate their potential for clinical translation, addressing both opportunities and challenges.

Keywords:  Cancer immunotherapy; Metabolism regulation; Nanotherapeutics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jconrel.2025.114587
Front Immunol. 2025 ;16 1727125

CD147 at the crossroads of glycoprotein networks, metabolic reprogramming, and metastatic progression.

Tz-Syuan Su, Jiunn-Wei Wang, Yu-Li Su, Ming-Hong Lin, Hsin-Ying Clair Chiou.

  CD147 (also known as EMMPRIN or Basigin), a transmembrane glycoprotein of the immunoglobulin superfamily, functions as a pivotal regulator of tumor progression. It coordinates key oncogenic processes-including metabolic adaptation, chemoresistance, angiogenesis, and immune modulation-through an extensive network of protein-protein interactions. Metabolic reprogramming not only reshapes the intrinsic metabolic circuitry of tumor cells but also promotes the establishment of a pre-metastatic niche that facilitates metastatic seeding and outgrowth via dynamic metabolic crosstalk with immune and stromal components. Here, we review current evidence showing that CD147 mediates PMN formation by promoting immune evasion, metabolic adaptation, and stromal remodeling. Through the coordination with membrane-associated glycoproteins-including CD44, epidermal growth factor receptor (EGFR), integrins, CD280 (uPARAP/Endo180/MRC2), and CD276, CD147 orchestrates intracellular signaling events that drive cancer cell metabolic adaptation. These interactions contribute to metabolic reprogramming across glucose, lipid, amino acid, and mitochondrial pathways, thereby linking CD147-mediated metabolic plasticity to tumor dissemination and metastasis. By integrating insights into immune and stromal modulation within the tumor microenvironment (TME), this review highlights the multifaceted roles of CD147 and its glycoprotein interactome in shaping the metastatic niche.

Keywords:  CD147; CD44; cancer metabolism; pre-metastatic niche formation; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1727125
Cell Death Dis. 2025 Dec 27.

A new strategy for CAR-T therapy in solid tumors: IL-15-autocrine signaling augments tumor stroma depletion and promotes a TSCM subset in the TME.

Yanyang Pang, Leiyuan Chen, Qinghui Sun, Na He, Zhiheng Lai, Xi Wang, Zhihao Xie, Wenli Yang, Wu Wang.

Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable therapeutic effects in treating hematologic cancers, its effectiveness in solid tumors remains significantly restricted. the primary reason is the immunosuppression mediated by the tumor microenvironment (TME), which leads to rapid exhaustion of infiltrating CAR-T cells. To enhance CAR-T cell efficacy against solid tumors, we pursued improvements in two aspects. First, we constructed fibroblast activation protein (FAP)-directed CAR-T cells to enhance their anti-CAF capability within the TME, thereby alleviating the immunosuppressive barrier. Second, we utilized IL-15, an efficient activator of CAR-T cells that inhibits activation-induced cell death, restores effector functions, and increases the proportion of the T stem cell memory (TSCM) subpopulation. In this study, we report the generation of FAP/IL-15 CAR-T cells, which target FAP and autonomously synthesize and secrete IL-15. Our data demonstrate that treatment with FAP/IL-15 CAR-T cells exhibited stronger activation characteristics in a FAP antigen-dependent manner, selectively targeting CAFs within the solid TME. Moreover, endogenous IL-15 secretion enabled CAR-T cells to adopt a TSCM-like phenotype with enhanced memory characteristics, thus improving cell survival, proliferation, activation, and therapeutic efficacy against solid tumors.

DOI: https://doi.org/10.1038/s41419-025-08405-2
Semin Oncol. 2025 Dec 02. pii: S0093-7754(25)00146-0. [Epub ahead of print]53(1): 152454

Immuno-oncology approaches to overcome T cell exhaustion in melanoma.

Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mohammad Y Alshahrani, Muzdalifa Mejbel Fedwi, Subbulakshmi Ganesan, Zahraa Abbas Al-Khafaji, Vimal Arora, Amrita Pal, Priya Priyadarshini Nayak, Sarvar Islomov, Chou-Yi Hsu.

  Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8+, CD4+, and Tregs) in melanoma immunity. CD8+ T cells are important effectors, as they primarily recognize and kill tumor cells. However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4+ T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity. This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes. However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence. Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.

Keywords:  Exhaustion; Immunity; Immunotherapy; Melanoma; T cell

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152454
Front Psychiatry. 2025 ;16 1683058

The role of depression in the progression of tumor cell inflammation and the potential regulatory mechanisms of aerobic exercise: a narrative review from molecular and cellular perspectives.

Mingming Ren, Jianda Kong, Chuankai Luan, Yujing Mu.

  There is a tight correlation between depression, and tumor progression, particularly via the regulation of the immune system, and inflammatory responses. Chronic inflammation is a member of the core causes in the tumor microenvironment, which can promote tumor initiation, progression, and immune evasion. An increasing body of literature has reported that aerobic exercise (AE), as a non-pharmacological intervention, can display potential in anti-tumor therapy by modulating the immune system, delaying chronic inflammation, and increasing neurotransmitter balance. However, it is worth noting that extreme AE may cause negative influences, such as immunosuppression, which influences its anti-tumor efficacy. Our review aims to investigate how depression influences the inflammatory progression of tumor cells via immune regulation, and the potential regulatory processes of AE in this mechanism. Moreover, we further explore the potential of AE in tumor treatment, and delves into its potential deleterious impacts. via this literature review, together with perspectives from molecular, and cellular biology, notably, our review explores the influences of depression, and AE on the tumor microenvironment, and immune responses. It centers on the contribution of AE in modulating immune cell functions, delaying chronic inflammatory responses, and increasing neurotransmitter balance. Depression promotes inflammatory responses in the tumor microenvironment via neurotransmitter imbalance, abnormal activation of the hypothalamic-pituitary-adrenal axis, and immune system dysregulation, hence triggering tumor growth, and metastasis. AE can positively modulate the immune system, decrease inflammation, as well as improve tumor immune surveillance function. Moderate AE modulates immune responses in the tumor microenvironment in the context of enhancing the activity of immune cells, lowering the levels of pro-inflammatory factors, and improving the production of anti-inflammatory factors, hence blocking the growth, and spread of tumor cells. However, extreme AE may cause immunosuppression, influencing anti-tumor influences, so individualized changes to the intensity, and frequency of exercise interventions are needed.

Keywords:  aerobic exercise; anti-tumor therapy; depression; immune regulation; inflammatory response; tumor progression

DOI:  https://doi.org/10.3389/fpsyt.2025.1683058
J Immunother Cancer. 2025 Dec 31. pii: e013040. [Epub ahead of print]13(12):

Chimeric antigen receptor dendritic cells suppress melanoma growth in preclinical cancer models.

Julia Minnee, Wallace Zh Wong, Benjamin S Russell, Jose Lm Semana, Ruofan Li, Nathaniel R Landau, Takuya Tada.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has been successful for the treatment of hematological cancers but less effective against solid tumors, a phenomenon that results from the immunosuppressive nature of the tumor microenvironment. As a strategy to improve the treatment of solid tumors, we applied CAR therapy to dendritic cells (DCs) to generate CAR-DCs. The CAR targeted the human epidermal growth factor receptor 2 (HER2) which is overexpressed in breast cancer to defeat the immunosuppressive nature of the tumor microenvironment.
METHODS: CAR-DCs were generated by lentiviral vector transduction of SAMHD1 knock-out murine bone marrow-derived DCs. The vectors coexpressed CD40L and a soluble form of programmed cell death 1 (PD-1), a checkpoint inhibitor. To increase the durability of CAR-DCs, a gene encoding the cytokine GM-CSF was introduced into the CAR vector. The CAR-DCs were injected into mice bearing B16.HER2 melanoma tumors. Tumor growth was measured, and T cell functionality was determined by IFNγ expression and in vitro cytolytic assay.
RESULTS: CAR-DCs suppressed the growth of B16.HER2 tumors and induced the proliferation and activation of tumor-infiltrating cytolytic CD8+T cells. The PD-1 checkpoint inhibitor further augmented the antitumor response and prevented T cell exhaustion. Vectored expression of GM-CSF increased the durability of the antitumor response.
CONCLUSIONS: CAR-DCs could be an effective strategy for therapies against solid tumors that should be further explored. The approach relies on the antigen-presenting ability of DCs and their role in T cell activation and can be coupled with checkpoint inhibition in place of monoclonal antibody treatment.

Keywords:  Chimeric antigen receptor - CAR; Dendritic; Immune Checkpoint Inhibitor; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2025-013040
Mol Cell Biochem. 2026 Jan 02.

Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.

Mahdi Maleki Aghdam, Lotfollah Rezagholizadeh, Aliakbar Fazaeli, Alireza Moradi, Masoud Ojarudi.



Keywords:  Immunometabolism; Metabolic reprogramming; Nutrient-sensing pathways; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11010-025-05462-1
Int J Mol Sci. 2025 Dec 16. pii: 12110. [Epub ahead of print]26(24):

Deciphering the Role of Mast Cells in HPV-Related Cancers.

Zyanya P Espinosa-Riquer, J Omar Muñoz-Bello, Claudia González-Espinosa, Alfredo Ibarra-Sánchez, Marcela Lizano.

  Human Papillomavirus (HPV)-related cancers constitute a major global health problem, accounting for 4.5% of all human cancers. Studying the composition of the tumor microenvironment (TME) of HPV-related cancers may help develop therapeutic strategies or identify prognostic biomarkers with potential clinical significance. Among all the components of TME, mast cells (MCs) appear to be particularly relevant in HPV-related tumors. MCs are myeloid-derived immune cells that release a wide range of inflammatory mediators. It is now recognized that these immune cells are important players within the TME, where they can exert both anti- and pro-tumor activities depending on the type of MC-derived inflammatory mediators released. MCs may play an important role in the processes associated with cell transformation, development, and the progression of HPV-associated tumors; however, their specific functions in these neoplasms are not yet fully understood. This review addresses the current state of knowledge on MCs and their contribution to the molecular biology of HPV-related cancers. In addition, it highlights MCs' roles in the pro- or anti-tumor paradigm and discusses their emerging potential as therapeutic targets or prognostic biomarkers.

Keywords:  HNSCC; HPV; anti-tumoral; cancer; cervical cancer; mast cells; oncogenes; oncoproteins; pro-tumoral

DOI:  https://doi.org/10.3390/ijms262412110
Mol Cancer Ther. 2025 Dec 31.

Non-Glycosylated, Legumain-Cleavable ISACs Drive Potent Anti-Tumor Immunotherapy via a Bystander Effect.

Anqi Zhang, Mohan Reddy Mullapudi, Lina Wu, Michele Yi, Mohammad Asikur Rahman, Aiman A Yaseen, H Kayla Zhong, Tracy A Brooks, L Nathan Tumey.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer, with poor prognosis driven by late diagnosis, therapeutic resistance, and an immunosuppressive tumor microenvironment. Interactions between tumor cells and immune cells promote immune evasion and tumor progression, limiting the efficacy of immune checkpoint blockade and other immunotherapies. Given the high expression of TROP2 in PDAC, we developed a TROP2-targeted TLR7 agonist (E104) designed for selective accumulation within the tumor microenvironment to activate antitumor immunity. Although antibody bioactivity is traditionally linked to Fcγ receptor (FcγR) engagement and recruitment of effector cells, our legumain-cleavable, non-glycosylated immune-stimulating antibody conjugates (NG-ISACs) induce robust myeloid activation, cytokine release, and tumor regression without FcγR-mediated functions of natural killer cells or macrophages. Rather, NG-anti-TROP2-E104-ISACs depend on tumor antigen recognition and TLR7 activation, not FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP), to elicit tumor regression and adaptive immunity, as evidenced by anti-TROP2 antibody generation in a syngeneic model. By incorporating the cell-permeable E104 payload with bystander activity, NG-ISACs can activate immune responses independently of FcγR binding. In vitro, NG-anti-TROP2-E104-ISACs bypass FcγRIIa-mediated ADCC and FcγRIIIa-mediated ADCP while maintaining potency in co-cultures of TROP2-positive tumor and effector cells. Moreover, NG-anti-TROP2-E104-ISACs display reduced acute toxicity compared to glycosylated counterparts. Together, these findings delineate the bystander mechanism underlying FcγR-independent immune stimulation and establish a framework for designing ISACs with improved safety.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1153
Crit Rev Oncol Hematol. 2025 Dec 25. pii: S1040-8428(25)00487-1. [Epub ahead of print]218 105099

Mechanical microenvironment and its role in hepatocellular carcinoma oncogenesis and progression.

Xiaojia Guo, Yuanyuan Xie, Rongmin Qian, Jing Li, Junling Shi, Qingsheng Huang, Dongyan Shao.

  Hepatocellular carcinoma (HCC) ranks among the most prevalent types of tumors globally. There is no effective cure for HCC in clinical practice, which emphasizes the need to conduct in-depth research into mechanisms that can facilitate the development of effective treatments for HCC. Numerous studies have demonstrated that the mechanical factors within an HCC microenvironment, such as matrix stiffness and fluid shear stress, have significant effects on the different stages of development. And these mechanical factors are also involved in the immune-evasion process of HCC, which affects the progression of HCC. However, current reviews related to HCC mainly focus on discussing the influence of mechanical factors on various cells in the tumor microenvironment, with less consideration of the impact of mechanical factors on each stage of tumor development. Therefore, this review discussed the influence of these different mechanical factors on the various stages of HCC development, including the initiation, proliferation, angiogenesis, migration, invasion, metastasis, drug resistance and immune escape. This review provides a theoretical basis for future in-depth investigations into the relationship between mechanical factors and HCC.

Keywords:  Fluid shear stress; Hepatocellular carcinoma; Immune evasion; Interstitial fluid pressure; Matrix stiffness; Tumor progression

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105099
Cell Metab. 2025 Dec 29. pii: S1550-4131(25)00530-3. [Epub ahead of print]

Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.

Jianbiao Xiao, Zhiyang Li, Yi Ding, Kejin Zhu, Zhihao Zheng, Yaowei Zhang, Jiawen Weng, Feifei Wang, Yuqin Zhang, Sisi Zeng, Minxing Qiu, Zhaowen Zhang, Zhizhang Wang, Li Liang.

  Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.

Keywords:  CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine

DOI:  https://doi.org/10.1016/j.cmet.2025.11.016
Mater Today Bio. 2025 Dec;35 102635

PH20-modified exosomes loaded curcumin inhibit desmoplastic breast cancer by breaking extracellular matrix barrier and normalizing cancer-associated fibroblasts.

Xiaoxia Xue, Xiaoyu Li, Meng Tian, Liuchunyang Yu, JinXiu Qian, Xiuyun Bai, Jue Yang, Rongjun Deng, Qiqiong Liu, Ying Xing, Yuxing Yao, Cheng Lu, Aiping Lyu, Yuanyan Liu.

  Triple-negative breast cancer (TNBC), a typical desmoplastic tumor, is characterized by dense fibrotic stroma enriched with cancer-associated fibroblasts (CAFs) and excessive extracellular matrix (ECM) deposition. Activated CAFs secrete abundant cytokine to promote tumor progression, while continuously recruit ECM proteins to form stiff pathological barriers that impede drug penetration and immune cell infiltration. In this work, we designed engineered exosomes co-modified with hyaluronidase PH20 (Exos-PH20) and curcumin (Cur) to specifically deliver Cur, aiming to breakthrough desmoplastic tumor microenvironment (TME) for deep tumor penetration, CAFs normalization rather than elimination, and amplification of anticancer efficacy. Results showed that Exos-PH20@Cur leverage the tumor-targeting capability of exosomes and PH20-mediated hyaluronan degradation to achieve deep intratumoral penetration. Meanwhile, the normalization of CAFs by suppressing PRMT5-strengthened Smad3-mediated fibrotic gene transcription, can alleviate TNBC fibrosis and even can disrupt TGF-β and IL-6 mediated crosstalk of CAFs with cancer cells to combat tumor invasion. As a result, the enhanced accumulation of Exos-PH20@Cur in tumor core, along with increased CD8+ T cells infiltration, contributed to effective cytotoxic inhibition on cancer cells. This green synthesized biocompatible nanoplatform offers a promising dual therapeutic strategy for remodeling desmoplastic TME and inhibiting tumor progression with effective drug delivery for improved TNBC therapeutic outcomes.

Keywords:  CAFs; Curcumin; Desmoplastic tumor microenvironment; Engineered exosomes; TNBC

DOI:  https://doi.org/10.1016/j.mtbio.2025.102635
iScience. 2025 Dec 19. 28(12): 114203

Advances in the clinical application of bispecific antibodies in cancer therapy.

Shiqi Zhou, Feng Li, Mengke Niu, Kongming Wu, Tianye Li, Ming Yi.

  Cancer immunotherapy has emerged as one of the most groundbreaking advancements. However, the tumor microenvironment (TME) is often dominated by various immunosuppressive factors, compromising the efficacy of single-target therapies, leading to non-responsiveness or resistance. Bispecific antibodies (BsAbs) represent an innovative immunotherapeutic strategy with enormous potential for improving cancer treatment outcomes. Unlike monoclonal antibodies, BsAbs can concurrently inhibit multiple pro-tumor pathways, target immune checkpoints to mitigate resistance, and bind to two distinct antigens, thereby enhancing specificity while minimizing off-target effects. Moreover, BsAbs are more cost-efficient and less toxic compared to the use of two separate monoclonal antibodies in combination. In recent decades, BsAbs have made remarkable progress in clinical development. Several BsAbs, such as blinatumomab, mosunetuzumab, teclistamab, glofitamab, epcoritamab, talquetamab, ivonescimab, cadonilimab, tarlatamab, zenocutuzumab, and catumaxomab, have achieved notable success in clinical trials. This review highlights clinically approved BsAbs and provides a comprehensive summary of their therapeutic applications in cancer treatment.

Keywords:  Cellular therapy; Oncology; Therapeutics

DOI:  https://doi.org/10.1016/j.isci.2025.114203
J Adv Res. 2025 Dec 30. pii: S2090-1232(25)01040-9. [Epub ahead of print]

Tryptophan metabolism in tumor microenvironment and therapeutic Implications.

Junjie Wen, Junqing Jiang, Xianglong Ma, Wang Wei, Xiaoli Wu, Yan Yu, Limin Xia.

   BACKGROUND: Tryptophan (Trp) catabolism has been recognized as a key immunosuppressive axis in cancer. However, this largely centered on indoleamine-2,3-dioxygenase 1 (IDO1). The clinical failure of IDO1 inhibitors has exposed the limitations of this reductionist view.
AIM OF REVIEW: To re-synthesize current knowledge into a further understanding of Trp metabolism, and propose biomarker-guided, multi-node intervention strategies that can resurrect Trp metabolism as a precision immuno-oncology target. Key Scientific Concepts of Review: This review comprehensively describes the pathways of Trp metabolism in the human body and the key enzymes that can serve as therapeutic targets, thus proposing the possibility of multi enzyme combined inhibition. Second, we synthesize how Trp metabolites can modulate the functionality of immune cells, mainly T cells, within the tumor microenvironment, thereby affecting tumor immune surveillance and the efficacy of immunotherapy. Then we discuss how tumor cells manipulate Trp metabolic pathways to enhance their survival and metastasis. We also propose a new framework for targeting Trp metabolism, such as combining enzymes inhibitors or Aryl hydrocarbon receptor (AhR) antagonists with immune checkpoint blockade. By shifting from "IDO1-focus" paradigms to comprehensive metabolic interventions, we may release more potential of Trp modulation in cancer immunotherapy.

Keywords:  Aryl hydrocarbon receptor; Cancer therapy; Tryptophan metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jare.2025.12.049
Pathol Res Pract. 2025 Dec 24. pii: S0344-0338(25)00532-1. [Epub ahead of print]278 156339

Extracellular vesicles in tumor microenvironment modulation and clinical diagnosis.

Huan Liu, Dong Niu, Tong-Yao Yu, Yu-Hua Wang, Kun-Lin Ran, Yan-Hua Liu, Da-Chuan Yin, Chen-Yan Zhang.

  Extracellular vesicles (EVs) are key drivers of tumor metastasis and colonization. Their cargo, consisting of proteins, nucleic acids, and other biomolecules, functions as molecular messengers that trigger the epithelial-mesenchymal transition (EMT) process in tumor cells and facilitate immune evasion by releasing immunosuppressive factors to promote immune escape. Additionally, EVs influence intercellular interactions within the tumor microenvironment, facilitating angiogenesis, increasing vascular permeability, and supplying nutrients and oxygen to support tumor growth and metastasis. During metastasis, EVs protect circulating tumor cells (CTCs) from shear forces in the vascular network and attacks from the immune system. Furthermore, tumor-derived EVs facilitate the establishment of pre-metastatic niches (PMNs), thereby facilitating organ-specific metastasis. In this review, we overview the biogenesis and functions of EVs, as well as various factors that regulate their secretion. We systematically review tumor-derived EV functions in tumor progression, and also the effects of their interactions with other cells (such as adipocytes, immune cells, fibroblasts, and mesenchymal stem cells) in the tumor microenvironment was clarified. Additionally, we evaluate the diagnostic and prognostic potential of EVs as biomarkers for early tumor detection. The review also summarizes validated EV-associated biomarkers, offering a valuable foundation for the development of EV-based strategies in cancer diagnosis and therapy.

Keywords:  Biomarker; Extracellular vesicles; Neoplasm diagnosis; Neoplasm prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2025.156339
Front Immunol. 2025 ;16 1726440

Targeting glioma-associated microglia and macrophages: a new frontier in glioblastoma immunotherapy.

Bingyang Wang, Cong Li, Jiatong Gu, Xiaojie Wang, Mingjuan Xun, Bin Jiang, Jun Yan.

  Glioblastoma (GBM), the most aggressive and lethal subtype of glioma, remains therapeutically intractable despite advances in surgical and chemo-radiotherapy interventions. The highly immunosuppressive tumor microenvironment (TME) contributes significantly to treatment resistance and tumor recurrence. Among the predominant immune constituents, glioma-associated microglia and macrophages (GAMs) constitute a major cellular compartment, exerting profound influence on tumor progression, immune evasion, angiogenesis, and therapeutic response. These myeloid populations, derived from both yolk sac-origin microglia and bone marrow-derived macrophages, exhibit remarkable functional plasticity and are actively recruited, polarized, and reprogrammed by tumor-intrinsic and environmental cues. Recent studies have elucidated a range of molecular pathways, including chemokine signaling, metabolic reprogramming, and epigenetic modulation, that govern GAM behavior and sustain their tumor-supportive phenotype. Therapeutic strategies targeting GAM recruitment, depletion, or functional re-education toward an anti-tumor state are emerging as promising adjuncts to conventional and immune-based therapies. This review comprehensively explores the ontogeny, regulatory networks, and pathological roles of GAMs in GBM, with particular emphasis on novel immunotherapeutic approaches, including CSF-1R blockade, nanoparticle-mediated reprogramming, and oncolytic virotherapy. A deeper understanding of GAM-TME interactions will be critical to overcoming immunotherapy resistance and advancing precision immunomodulation in GBM.

Keywords:  glioblastoma; glioma-associated microglia/macrophages; immune evasion; immunotherapeutic strategies; polarization; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1726440