bims-flamet 2026-02-15 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–02–15
34 papers selected by
Peio Azcoaga, Biodonostia HRI

New insights into the tumor immune microenvironment and immunotherapy of thyroid cancer.
m6A RNA modification and myeloid-derived suppressor cells: mechanistic insights and clinical prospects.
Immune-Centered Cross-Talk Between Cancer Cells and the Tumor Microenvironment-Implications for Therapy.
Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
VISTA: bridging gaps in cancer immunotherapy.
Unraveling immune evasion in the tumor microenvironment: Mechanisms, therapeutic strategies, and future directions in cancer immunotherapy.
Targeting the Tumor Microenvironment in Triple-Negative Breast Cancer: Emerging Roles of Monoclonal Antibodies and Immune Modulation.
MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.
Assays to examine lymphocyte invasion.
Epithelial-mesenchymal transition and cancer-associated fibroblasts in tumor progression and therapy resistance: mechanistic convergence and therapeutic opportunities.
The role of lactic acid metabolism in anti-tumor immunity.
HBV reprograms the tumor microenvironment in hepatocellular carcinoma: mechanisms and therapeutic implications.
Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.
Methodological advances to analyze cancer-associated fibroblast-derived ECM effects on macrophage polarization.
An immunostimulant nanomedicine enhances radioimmunotherapy by remodeling the tumor immunosuppressive landscape after radiotherapy.
Rewiring tumor-associated macrophages in hepatocellular carcinoma.
Sublethal heat stress synergizes with the tumor microenvironment to drive recurrence of hepatocellular carcinoma after thermal ablation: mechanisms, molecular predictors, and targeted interventions.
Drug-free Immunotherapeutic Biomimetic Nanoparticles for Treating Triple-Negative Breast Cancer.
Tumor-Associated Neutrophils and Desmoplastic Reaction in the Breast Cancer Tumor Microenvironment: A Comprehensive Review.
Colorectal cancer stem cells in the tumor microenvironmental niche: Mechanistic insights and emerging therapies.
The distinct roles of ROS in tumor immunity: from mechanisms to immunotherapeutic applications.
Surviving the siege: A review on the metabolic hallmarks of cancer dormancy.
Nanomaterial-Enabled Modulation of Tumor-Associated Macrophages and Dendritic Cells to Enhance Cancer Immunotherapy.
CLK1 Promotes Myeloid-Derived Suppressor Cell Trafficking and Reprograms the Tumor Microenvironment by activating Hippo/YAP signaling in Colorectal Cancer.
Molecular heterogeneity of Glioblastoma-associated microglia and macrophages and myeloid-derived suppressor cells: Insights from single-cell omics and therapeutic implications.
Induction of immunogenic cell death by active components of natural products reshaping the tumor microenvironment for enhanced antitumor immunity.
Targeting Matrix Stiffness and Mechanotransduction in Breast Cancer: Implications for Emerging Therapies.
Impact of the intratumoral resident microbiome on the immune microenvironment of malignant tumors (Review).
LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
CAR-macrophages: a new chapter in cancer immunotherapy.
Targeting Macrophages in Immunotherapy: The Ascent of CAR-Macrophages.
Association of METTL14 expression with prognosis and immunotherapy in breast cancer.
Emerging perspectives on metabolic reprogramming in the microenvironment of ovarian cancer metastasis.
Mitochondrial Transfer in the Tumor Microenvironment.

Front Immunol. 2026 ;17 1699500

New insights into the tumor immune microenvironment and immunotherapy of thyroid cancer.

Jia-Jia Du, Jian Wang, Kai Ma, Peng Ma.

  Thyroid cancer (TC) is the most common malignant tumor of the endocrine system. Although most cases have a favorable prognosis, some patients may be resistant to treatment or exhibit aggressive behavior. The tumor microenvironment (TME) network, composed of stromal cells, immune cells, vascular cells, and cancer cells, has become a key factor in the development of TC. The TME affects the biological behavior of TC through different immune states. TC cells can suppress antitumor immune response by promoting an immunosuppressive microenvironment, such as through the recruitment of tumor-associated macrophages (TAMs), tumor-associated mast cells (TAMCs), myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs), and regulatory T cells (Tregs), among other immunosuppressive cells. They also express negative immune checkpoints such as programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and immunosuppressive enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1). This suggests that immunotherapy may be a promising treatment for TC, especially for patients who do not respond to traditional therapies. This article focuses on the interaction mechanism of cells and molecules in the tumor immune microenvironment (TiME) involved in the occurrence and development of TC and analyzes its potential value as a therapeutic target. In addition, the latest clinical trials related to immunotherapy for TC are summarized.

Keywords:  PD-L1; immunotherapy; metabolic reprogramming; thyroid cancer; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1699500
Front Immunol. 2026 ;17 1694842

m6A RNA modification and myeloid-derived suppressor cells: mechanistic insights and clinical prospects.

Chunhong Li, Xiulin Jiang, Yixiao Yuan, Xi Chen, Shanrui Pu, Kun Lian, Lihua Li, Qiang Wang.

  N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in eukaryotic mRNA, extensively involved in RNA splicing, export, stability, and translation. In recent years, accumulating evidence has demonstrated that m6A modification plays a critical role in regulating the differentiation and function of immune cells. Among these, myeloid-derived suppressor cells (MDSCs), as a key immunosuppressive population within the tumor microenvironment (TME), accelerate tumor progression by inhibiting T cell activity and promoting immune evasion and therapy resistance. Emerging studies indicate that m6A modification modulates the development, accumulation, and immunosuppressive function of MDSCs, thereby contributing to tumor initiation and progression. This review provides a narrative overview of the current evidence regarding the crosstalk between m6A modification and MDSCs, with a focus on the underlying molecular mechanisms and their potential implications for cancer immunotherapy. Furthermore, we discuss future research directions and the challenges associated with clinical translation.

Keywords:  MDSC; epitranscriptome; immunotherapy; m6A modification; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1694842
Cancers (Basel). 2026 Jan 23. pii: 344. [Epub ahead of print]18(3):

Immune-Centered Cross-Talk Between Cancer Cells and the Tumor Microenvironment-Implications for Therapy.

Eliza Turlej, Aleksandra Domaradzka, Rostyslav Koksharov, Agnieszka Gizak.

  The tumor microenvironment (TME), composed of various immune and non-immune cells, as well as cancer stem cells, plays a critical role not only in promoting cancer cell proliferation and metastasis but also in modulating therapeutic response. A wide range of therapeutic strategies targeting the TME are currently employed in cancer treatment, including standard chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapies, agents targeting cancer-associated fibroblasts (CAFs), oncolytic viruses (OVs), cold atmospheric plasma therapy, and nanovaccines. This review provides a comprehensive overview of the influence of the TME on cancer sensitivity to these therapies across all types of solid tumors.

Keywords:  anti-cancer therapies; cancers; immune cells; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18030344
Exp Mol Med. 2026 Feb 13.

Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.

Tae Hyun Kim, Seong Hun Lim, Hyesung Lee, Young Chan Chae, Do Sik Min.

The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal-immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.

DOI: https://doi.org/10.1038/s12276-026-01650-1
Discov Oncol. 2026 Feb 10.

VISTA: bridging gaps in cancer immunotherapy.

Aida Khademolhosseini, Mina Roshan Zamir, Ali Moazzeni, Zahra Mansourabadi, Elahe Safari.

  Tumor microenvironment (TME) is complicated by the interaction of different cells of immune system, stromal components, and tumor-associated elements. Immune cells largely influence tumor progression by the means of various activating and inhibitory mechanisms including, immune checkpoint molecules. These molecules have been targeted for treating different types of cancers. For instance, blocking antibodies against CTLA-4, PD-1, or PD-L1 have elicited durable clinical responses and remarkable efficacy. These antibodies have also led to long-term remissions in a subset of patients, especially when used in combination therapies. V-domain immunoglobulin suppressor of T cell activation (VISTA) as a negative regulator of the immune system is expressed on multiple immune cell subsets including, myeloid-derived suppressor cells (MDSCs), macrophages, and lymphocytes. VISTA exerts regulatory effects and modulates T cell function and has shown prognostic significance in different cancers, leading to an increased attention regarding its suppressive role in the context of cancer. In this review, we will summarize the VISTA structure, ligands, role in the TME, and expression on immune cells. Furthermore, the significance of VISTA expression in the prognosis of cancer and its role in cancer immunotherapy, tumor resistance and ongoing clinical trials will be discussed.

Keywords:  Cancer; Immune checkpoint; Immunotherapy; Tumor microenvironment; VISTA

DOI:  https://doi.org/10.1007/s12672-026-04407-4
Mol Immunol. 2026 Feb 11. pii: S0161-5890(26)00019-2. [Epub ahead of print]191 70-78

Unraveling immune evasion in the tumor microenvironment: Mechanisms, therapeutic strategies, and future directions in cancer immunotherapy.

Geeth Harini Chandrasekar.

  The immune evasion that is encouraged by the tumor microenvironment (TME) is a key factor in the failure of cancer immunotherapies. This review addresses how tumor cells avoid immune surveillance, which is critically dependent on cellular and molecular events associated with immune checkpoint signaling, the capture of immune surveillance cells, metabolic restructuring, and physical and hypoxic barriers. We also discuss the latest therapeutic options, including immune checkpoint blockers, metabolic and angiogenic combination therapies, and Macrophage reprogramming of tumors. Nonetheless, such challenges as therapeutic resistance and patient heterogeneity are still significant challenges. In the future, individualized immunotherapy with the use of precision oncology tools that integrate multi-omics profiling, artificial intelligence, and manipulation of the gut microbiome a promising opportunity. A better understanding of the dynamic TME and the individualized immune landscape is the key to effective immunotherapy and the attainment of durable clinical responses to various types of cancers.

Keywords:  Cancer immunotherapy; Immune evasion; Myeloid-derived suppressor cells (MDSCs); Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1016/j.molimm.2026.01.013
Cancers (Basel). 2026 Jan 28. pii: 412. [Epub ahead of print]18(3):

Targeting the Tumor Microenvironment in Triple-Negative Breast Cancer: Emerging Roles of Monoclonal Antibodies and Immune Modulation.

Stephanie Figueroa, Niradiz Reyes, Raj K Tiwari, Jan Geliebter.

  Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This molecular phenotype narrows the availability of targeted therapies and contributes to high rates of early relapse, therapeutic resistance, and poor clinical outcomes. Mounting evidence pinpoints the tumor microenvironment (TME) as a central driver of TNBC progression, immune evasion, and resistance to treatment. The TME encompasses a complex and dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that collectively shape tumor behavior and influence therapeutic response. Notably, TNBC often displays an immunologically active microenvironment, marked by high levels of tumor-infiltrating lymphocytes and immune checkpoint expression, opening a window for immune-based therapeutic strategies. This narrative review summarizes current knowledge on the cellular, molecular, and structural features of the TNBC tumor microenvironment, with particular focus on immunosuppressive mechanisms mediated by tumor-associated macrophages, myeloid-derived suppressor cells, cancer-associated fibroblasts, and dysfunctional T cells. We describe the clinical development and therapeutic impact of monoclonal antibodies, including immune checkpoint inhibitors and antibody-drug conjugates. Additionally, we discuss strategies aimed at modulating the TME to enhance monoclonal antibody efficacy, including immune cell reprogramming, extracellular matrix remodeling, cytokine/chemokine blockade, and combination treatment strategies. Finally, we highlight the role of biomarker-driven patient stratification and personalized therapeutic strategies, addressing current challenges and future directions in TME-targeted drug development. Together, these insights underscore the potential of integrating immune modulation and monoclonal antibody-based therapies to improve outcomes for TNBC patients.

Keywords:  monoclonal antibodies (mAbs); triple-negative breast cancer (TNBC); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers18030412
Front Immunol. 2026 ;17 1738440

MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.

Íñigo González-Larreategui, Manrique Valdés-Bango Martín, Sílvia Casacuberta-Serra, Laura Soucek.

  Immunotherapies have transformed cancer treatment by harnessing the immune system to recognize and eliminate malignant cells, offering durable clinical benefit across diverse tumor types. Despite successes with immune checkpoint inhibitors (ICIs) and other strategies like cytokines, oncolytic viruses, cancer vaccines, bispecific antibodies, and adoptive cell therapies, substantial fractions of patients still fail to respond or develop resistance. The oncogene MYC, deregulated in ~70% of human cancers, has emerged as a central driver of immune evasion and a key contributor to immunotherapy failure. MYC regulates broad transcriptional networks controlling proliferation, metabolism, angiogenesis, and cell survival, while also orchestrating profound remodeling of the tumor microenvironment (TME). Mechanistically, oncogenic MYC suppresses antigen processing and presentation, attenuates interferon signaling, and upregulates immune checkpoints such as PD-L1 and CD47. Concurrently, MYC stimulates secretion of immunosuppressive cytokines and chemokines that recruit regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, while driving metabolic reprogramming that fosters nutrient competition, hypoxia, and acidosis, impairing effector T- and NK-cell function. Through these pathways, MYC promotes primary, adaptive, and acquired resistance to immunotherapy. Targeting MYC, directly or indirectly, holds promise to restore immune surveillance and potentiate immunotherapeutic efficacy. This review highlights MYC as a master regulator of tumor-immune interactions and underscores the therapeutic potential of MYC inhibition to overcome resistance and expand the clinical impact of cancer immunotherapy.

Keywords:  MYC; immune evasion; resistance; targeted therapies; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1738440
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00208-0. [Epub ahead of print]202 241-251

Assays to examine lymphocyte invasion.

Alexander A Lekan, Rachael E Maynard, Louis M Weiner.

  The immune system plays a critical role in a number of pathologic conditions, including infection, autoimmunity, and cancer. The migratory capacity of immune cells is essential to their ability to reach and invade into sites of infection, tissue damage, or solid tumors. Notably, studying the migration and invasion of immune cells has become increasingly important in the treatment of cancer. Immunotherapy has revolutionized the treatment of cancer. One critical barrier to the efficacy of immunotherapy, especially in solid tumors, is the ability of immune cells, specifically T and Natural Killer (NK) cells, to infiltrate into the tumor microenvironment (TME). Because of this, it has become increasingly important to study the invasive and migratory capabilities of immune cells in the context of cancer. Additionally, in vitro models that better recapitulate the TME are necessary in order to examine the invasion of human immune cells. Here, we describe 2D and 3D methods that can be used to examine the migratory and invasive capabilities of immune cells. These techniques have been adapted from previously described techniques.

Keywords:  Droplet assay; Extracellular matrix; Immune cells; Spheroid assay; Transwell invasion assay; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2025.10.008
Clin Transl Oncol. 2026 Feb 11.

Epithelial-mesenchymal transition and cancer-associated fibroblasts in tumor progression and therapy resistance: mechanistic convergence and therapeutic opportunities.

Dhiraj Kumar Singh, Rashmi Gupta, Umesh Kumar, Saurabh Gupta.

  Cancer progression and treatment failure are driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) represent two interlinked mechanisms that promote tumor invasion, metastatic dissemination, stemness, immune evasion, and resistance to therapy. EMT is regulated by transcription factors, such as Snail, ZEB, and Twist, and by signaling pathways including TGF-β, Wnt/β-catenin, and Notch, enabling cancer cells to adopt hybrid epithelial-mesenchymal states that confer phenotypic plasticity and drug tolerance. CAFs, derived from multiple cellular sources, further reinforce EMT programs through paracrine signaling, extracellular matrix remodeling, and metabolic reprogramming. This review critically synthesizes current evidence on EMT-CAF crosstalk in oncogenesis and therapeutic resistance, highlighting emerging clinical strategies, translational challenges, and lessons from failed or limited therapeutic approaches. By emphasizing EMT plasticity and CAF heterogeneity as convergent drivers of tumor adaptability, this work provides a refined framework for developing rational combination therapies targeting both cancer cells and their supportive stroma.

Keywords:  Cancer; Cell signaling; EMT; Fibroblast; Notch; TGF-β1; Tumor microenvironment; Wnt

DOI:  https://doi.org/10.1007/s12094-026-04255-2
Crit Rev Oncol Hematol. 2026 Feb 06. pii: S1040-8428(26)00070-3. [Epub ahead of print]221 105183

The role of lactic acid metabolism in anti-tumor immunity.

Zhenhao Wang, Hanlin Du, Zhuming Yang, Yuanyuan Zhang, Zhenya Hong.

  Recent studies have highlighted the pivotal role of lactate metabolism in key oncological processes, such as tumor proliferation, resistance and immune evasion. The discovery of histone lactylation pathways has further underscored the essential link between cellular energy metabolism and epigenetics, offering new insights into cancer biology. This review provides a systematic overview of lactate-immune crosstalk within the tumor microenvironment (TME), discusses the clinical relevance of lactate metabolism and lactylation biomarkers, and highlights emerging therapeutic strategies that target lactate-related pathways. By elucidating the lactate-regulated networks in cancer progression, this review offers insights into the underlying molecular mechanisms and potential pathways for the development of targeted therapies.

Keywords:  Immunity; Lactate; Metabolism; TME

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105183
Clin Exp Med. 2026 Feb 11.

HBV reprograms the tumor microenvironment in hepatocellular carcinoma: mechanisms and therapeutic implications.

Xiaodong Shen, Hechen Huang, Jianpeng Sheng, Xiaofeng Tang.

  Hepatitis B virus (HBV) infection is an important worldwide health issue and attribute to hepatocellular carcinoma (HCC) via direct oncogenic and indirect mechanisms. HBV reprograms the tumor microenvironment (TME) through immunosuppression, metabolic adaptation, and stromal remodel, allowing tumor promotion and immune evasion. This review examines HBV-induced TME changes, including epigenetic dysregulation, immune cell dysfunction, and fibrosis, as well as new therapeutic options including immune checkpoint blockade, adoptive cell therapy, and metabolic targeting to improve outcomes in HBV-related HCC.

Keywords:  Hepatitis B virus (HBV); Hepatocellular carcinoma (HCC); Immunotherapy; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s10238-025-01851-4
Genes Dis. 2026 May;13(3): 101834

Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.

Zizhuo Li, Jiapeng Deng, Hai Wang, Tao Liu, Yuyang Zhou, Pei Ouyang, Xuan Liang, Xian Zhang, Songtao Qi, Yaomin Li.

  As a critical metabolite in the tumor microenvironment, glutamine plays a crucial role in tumor progression, and its dual effects on promoting and inhibiting tumors have garnered increasing attention in recent years. Glutamine metabolism in tumor cells has been extensively studied; however, there is currently a lack of a comprehensive description of how it interacts with tumor stromal components in the tumor microenvironment. This review focuses on the interaction of glutamine metabolism and a range of tumor stromal components, such as macrophages, dendritic cells, T cells, fibroblasts, collagen, and blood vessels in the tumor microenvironment, as well as a summary of current prospective anti-tumor therapeutics targeting glutamine metabolism. Furthermore, this study discusses the shortcomings of mechanism research, metabolic complexity, and metabolic therapy for glutamine metabolism and proposes future research directions that are expected to provide a theoretical foundation for clinical cancer treatment strategies.

Keywords:  Anti-tumor therapy; Glutamine; Glutamine metabolism; Stromal cells; Tumor microenvironment; Tumor stromal components

DOI:  https://doi.org/10.1016/j.gendis.2025.101834
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00227-4. [Epub ahead of print]202 223-240

Methodological advances to analyze cancer-associated fibroblast-derived ECM effects on macrophage polarization.

Annalisa Tocci, Lorenzo Valenti, Nicla Porciello, Belinda Palermo, Anna Di Carlo, Francesca Di Modugno, Paola Nisticò.

  The tumor microenvironment (TME) represents a complex ecosystem composed of tumor cells and various non-cancerous cell types, embedded within an altered extracellular matrix (ECM). In solid tumors, the ECM plays multiple roles: it provides mechanical support, delivers signaling molecules and transmits biophysical stimuli that influence cellular functions. Various cell types, primarily cancer-associated fibroblasts (CAFs) and immune cells such as macrophages, actively participate in the secretion and remodeling of ECM. However, whether the ECM directly instructs or educates immune cells, particularly macrophages within the TME, remains poorly understood. Here, we present a protocol to investigate the impact of ECM derived from non-small cell lung cancer (NSCLC) CAFs on macrophage state.

Keywords:  Cancer-associated fibroblasts; Decellularized extracellular matrix; Extracellular matrix; Flow cytometry; Macrophage polarization; Macrophages; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/bs.mcb.2025.11.002
Acta Pharm Sin B. 2026 Feb;16(2): 1059-1073

An immunostimulant nanomedicine enhances radioimmunotherapy by remodeling the tumor immunosuppressive landscape after radiotherapy.

Mengwan Jiang, Mingyue Chen, Wen Zou, Yingxin Xie, Jinjin Shi, Junjie Liu, Aibing Chen, Xiu Zhao.

  Studies have shown that radiotherapy (RT) has powerful immune-stimulating effects. However, RT-mediated distal tumor regression is rare in clinical practice. Here, with an animal experimental model, we found that RT shaped an immunosuppressive landscape characterized by a high-influx of myeloid-derived suppressor cells (MDSCs), and the induction of immunologically silent tumor apoptosis, hindering the efficacy of radioimmunotherapy. To address this issue, we developed a spatiotemporally controlled nanomedicine for remodeling the immunosuppressive tumor microenvironment (TME) post-RT. Decitabine (DAC)-loaded ferritin (Ft) were crosslinked via an azobenzene linker, and meanwhile encapsulated with all-trans retinoic acid (ATRA) to construct a Ft@DAC@ATRA nanoassembly (denoted as FD@ATRA), which dissociated into monodispersive Ft@DAC units in hypoxia TME. The released ATRA could eliminate immunosuppressive MDSCs, and meanwhile Ft@DAC selectively induced immunogenic pyroptosis of the tumor by targeting the transferrin receptor 1 overexpressed on the tumor to effectively activate CD8+ T cells. FD@ATRA treatment reshaped the tumor immune landscape post-RT with an increase of 16.8% in tumor-infiltrating IFN-γ +CD8+ T cells. Moreover, FD@ATRA-enhanced RT remained effective in large, treatment-resistant tumors, and the inhibition rate of FD@ATRA-enhanced RT on distant tumors improved by 47% compared to the RT group alone, providing an effective therapeutic approach to improve the clinical outcomes of radioimmunotherapy.

Keywords:  Apoptosis; Breast cancer; Immune landscape; Myeloid-derived suppressor cells; Nanomedicine; Pyroptosis; Radiotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2025.11.012
Front Immunol. 2026 ;17 1775603

Rewiring tumor-associated macrophages in hepatocellular carcinoma.

Xue Han, Rui Jin.

  Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited responsiveness to immune checkpoint inhibitors (ICIs). Accumulating evidence indicates that tumor-associated macrophages (TAMs) are central regulators of the immunosuppressive tumor microenvironment (TME) and major contributors to immune escape and therapeutic resistance in HCC. TAMs arise from both circulating monocytes and tissue-resident macrophages and exhibit remarkable plasticity, adopting diverse polarization states in response to microenvironmental cues. Beyond the classical M1/M2 paradigm, single-cell and spatial technologies have revealed a continuum of TAM phenotypes with distinct transcriptional, metabolic, and functional properties. These heterogeneous TAM subsets orchestrate angiogenesis, fibrosis, immune suppression, and resistance to immunotherapy. Consequently, TAMs have emerged as attractive therapeutic targets. Strategies aimed at limiting monocyte recruitment, reprogramming M2-like TAMs toward antitumoral phenotypes, exploiting TAMs as drug delivery vehicles, and combining TAM-targeted interventions with ICIs, radiotherapy, anti-angiogenic agents, or nanobiotechnology have shown promising preclinical and early clinical efficacy. This review summarizes current advances in understanding TAM origin, polarization heterogeneity, and functional roles in HCC, and highlights emerging TAM-centered therapeutic strategies that may improve immunotherapy outcomes and enable more precise, durable treatment responses.

Keywords:  hepatocellular carcinoma; immune evasion; immunotherapy; polarization; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1775603
Cell Biol Toxicol. 2026 Feb 09.

Sublethal heat stress synergizes with the tumor microenvironment to drive recurrence of hepatocellular carcinoma after thermal ablation: mechanisms, molecular predictors, and targeted interventions.

Boran Li, Xiaoxi Bai, Liou Zhang.

  Although thermal ablation has emerged as a minimally invasive and effective local treatment for hepatocellular carcinoma (HCC), its high postoperative recurrence rate remains a major clinical challenge. Sublethal heat stress can induce residual tumor cells to upregulate factors such as heat shock proteins (HSPs) and hypoxia-inducible factor-1α (HIF-1α), enhancing their survival tolerance. This process synergizes with components of the tumor microenvironment (TME), including myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs), to collectively drive HCC recurrence. This article comprehensively reviews the research progress on the molecular mechanisms of tumor recurrence post-ablation, predictive biomarkers, and targeted therapeutic strategies. By deciphering multi-omics biomarkers, it provides new perspectives for predicting recurrence risk. Furthermore, this article also explores the potential of combination therapies, including targeting HSPs/HIF-1α, reversing immunosuppression, eliminating cancer stem cells (CSCs), and intervening in CAFs. This study provides a solid theoretical foundation for addressing the challenge of HCC recurrence, holding significant importance for improving patient prognosis and guiding clinical translation.

Keywords:  Heat shock proteins; Hepatocellular carcinoma; Thermal ablation; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10565-026-10160-9
ACS Nano. 2026 Feb 13.

Drug-free Immunotherapeutic Biomimetic Nanoparticles for Treating Triple-Negative Breast Cancer.

Ofri Vizenblit, Rawan Mhajne, Assaf Zinger.

  Tumor-associated macrophages (TAMs) are key drivers of tumor progression, metastasis, and immune evasion in triple-negative breast cancer (TNBC). Yet, most treatment strategies focus solely on tumor cells, neglecting the immunosuppressive tumor microenvironment (TME). Given the strong correlation between TAMs infiltration and poor prognosis, innovative therapeutic strategies that modulate TAMs dynamics are urgently needed. Here, we introduce MPsomes, macrophage biomimetic nanoparticles engineered to disrupt TAMs recruitment and alter the TME. Fabricated via a microfluidic approach, MPsomes integrate macrophage membrane proteins into lipid-based nanoparticles, retaining key surface markers essential for immune interactions. In vitro, MPsomes exhibited selective adhesion to inflamed endothelium, reducing macrophage recruitment in a flow chamber and Transwell migration assays. In vivo, systemic administration of MPsomes significantly reduced intratumoral TAMs populations and resulted in a pronounced inhibition of tumor growth compared to conventional liposomes. Notably, the therapeutic efficacy of MPsomes was comparable to that of FDA-approved anti-PD1 immunotherapy, further underscoring their potential as a drug-free, biomimetic alternative for TNBC treatment. These findings highlight the potential of MPsomes as a drug-free immunotherapeutic platform capable of reshaping the TME and inhibiting tumor progression, representing a previously unexplored therapeutic approach for TNBC.

Keywords:  biomimicry; immunotherapy; nanoparticles; triple-negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.5c18774
Cancers (Basel). 2026 Jan 27. pii: 404. [Epub ahead of print]18(3):

Tumor-Associated Neutrophils and Desmoplastic Reaction in the Breast Cancer Tumor Microenvironment: A Comprehensive Review.

Stavroula Papadopoulou, Vasiliki Michou, Arsenios Tsiotsias, Maria Tzitiridou-Chatzopoulou, Panagiotis Eskitzis.

  The evolving tumor microenvironment (TME) plays a critical role in breast cancer tumorigenesis, growth, and metastatic potential. This study focuses on two key components of the TME: tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR). We will analyze their multifaceted functions, emphasizing the significant mutual relationships among them, which dramatically affect disease outcomes and the effectiveness of treatments. TANs can either suppress or promote tumors, demonstrating notable functional flexibility in response to signals from their immediate environment. Concurrently, the proliferation of myofibroblasts and the extensive deposition of extracellular matrix (ECM), which characterize the DR, substantially alter the tumor's physical properties, increasing its stiffness. This increased stiffness significantly obstructs immune system cells from accessing the tumor, ultimately limiting the effectiveness of therapies and contributing to a more clinically aggressive tumor behavior. A comprehensive understanding of the interactions among TANs, the desmoplastic stroma, and other elements of the TME is critical for developing new predictive biomarkers and establishing more effective targeted therapies.

Keywords:  breast cancer; desmoplastic reaction (DR); extracellular matrix (ECM); tumor associated neutrophils (TANs); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers18030404
Biochim Biophys Acta Rev Cancer. 2026 Feb 10. pii: S0304-419X(26)00031-4. [Epub ahead of print] 189559

Colorectal cancer stem cells in the tumor microenvironmental niche: Mechanistic insights and emerging therapies.

Sandhiya Viswanathan, Madhuja Raha, Sudeshna Mishra, Srinivas Patnaik.

  Colorectal cancer (CRC) is a highly heterogenous disease, wherein a specific population of cancer stem cells (CSCs) are crucial in tumor initiation, therapeutic resistance, metastasis and disease progression. The tumor microenvironment (TME) plays a key role in the development of CRC stem cells (CCSCs) by sending signals and allowing cells to interact with each other, which helps to stem cells stay viable and regenerate. The ongoing interaction between CCSCs and diverse components of TME promotes treatment resistance and tumor recurrence. Recent advancements permitted the fabrication of three-dimensional (3D) tumor models using CCSCs. These models better replicate the in vivo TME and provide useful ways in personalized drug discovery and tumor biology. Therapy resistance in CCSCs is still an important concern in CRC therapy, because cells remain active, have good DNA repair systems, and interact with other cells in the TME. Targeted treatment techniques are being formulated to interrupt in various pathways, including DNA/RNA-based methods that inhibit oncogenic drivers or restore tumor suppressors in CCSCs. TME-targeted immunotherapies, including immune checkpoint inhibitors, T-cell-based treatments, and cytokine modulation, are shown potential in counteracting immune evasion by CCSCs. Numerous clinical trials are examining the effectiveness of inhibitors targeting CCSC-related pathways in metastatic CRC. This review comprehensively explores the evolution and role of CCSC within the TME, the development of 3D TME models from patient derived stem cells, mechanism of resistance and targeted immunotherapeutic strategies aimed at eradicating CSCSs to improve clinical outcomes in CRC.

Keywords:  Clinical research; Colon cancer; Stem cells; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189559
J Hematol Oncol. 2026 Feb 11.

The distinct roles of ROS in tumor immunity: from mechanisms to immunotherapeutic applications.

Jiayi Li, Chen Huang, Pan Tang, Ruiyan Wu, Quanyou Wu, Chenliang Zhang.

  Reactive oxygen species (ROS) are crucial signaling molecules that regulate diverse biological processes. In cancer, this duality gives rise to a central paradox. Moderate ROS levels support tumor proliferation and foster an immunosuppressive microenvironment, whereas excessive ROS can be therapeutically leveraged to trigger immunogenic cell death (ICD). Crucially, the outcome on immune cells, whether activation or exhaustion, is dictated by the subcellular localization and kinetics of ROS generation. This review critically examines this "ROS-Immune Mismatch," a new framework that highlights the differential redox sensitivities between tumor cells and key immune subsets. This differential sensitivity, where cytotoxic T cells (Teffs) are exhausted and immunosuppressive cells like regulatory T cells (Tregs) thrive, is a fundamental mechanism of immune evasion. We further analyze how emerging immunotherapies seek to exploit these redox dependencies to enhance therapeutic efficacy. Finally, we discuss major translational challenges, including off-target oxidative toxicity and redox heterogeneity within the tumor microenvironment (TME), and highlight future directions, such as intelligent nanomedicine and redox-reprogrammed cellular therapies, as promising strategies for next-generation ROS-targeted immunomodulation.

Keywords:  Reactive oxygen species; Tumor immunity; Tumor immunotherapy; Tumor microenvironment; Tumor therapy

DOI:  https://doi.org/10.1186/s13045-026-01780-z
Cancer Treat Res Commun. 2026 Jan 30. pii: S2468-2942(26)00034-1. [Epub ahead of print]47 101123

Surviving the siege: A review on the metabolic hallmarks of cancer dormancy.

Farah Djelti, Mostefa Hani, Yazid Chetbani, Ahmed Belaadi, Muhammad Imam Ammarullah.

  Cancer dormancy, a period of cellular hibernation, enables malignant cells to evade treatment and later initiate metastatic relapses, representing a central challenge in oncology. This review synthesizes the evidence that defines metabolic reprogramming as an essential hallmark of this persistent state. The authors find that dormant cells adopt a distinct bioenergetic identity, characterized by exceptional plasticity, which includes repurposed lipid pathways, a heightened capacity to neutralize oxidative stress, and a flexible reliance on both glycolytic and oxidative fuel sources. External cues from the tumor microenvironment (TME), where stromal-immune signaling and resource competition dictate metabolic fate, critically shape these adaptive programs. Although the specific metabolic profile can be heterogeneous and tissue-specific, the conserved reliance on certain pathways reveals a landscape of therapeutic liabilities. This review concludes that targeting these metabolic vulnerabilities is a highly promising strategy to forestall cancer recurrence. The path forward requires a focus on translating these findings through the clinical testing of metabolic modulators and the co-development of robust biomarkers to enable a new paradigm of personalized, preventive oncology.

Keywords:  Cancer; Metabolic plasticity; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.ctarc.2026.101123
Nanomaterials (Basel). 2026 Jan 27. pii: 172. [Epub ahead of print]16(3):

Nanomaterial-Enabled Modulation of Tumor-Associated Macrophages and Dendritic Cells to Enhance Cancer Immunotherapy.

Anbu Mozhi Thamizhchelvan, Kory Wells, Jacob Pham, Ashan Galhena, Woojin Kim.

  Tumor-associated macrophages (TAMs) and dendritic cells (DCs) play pivotal roles in shaping the tumor immune microenvironment, often contributing to immunosuppression and therapy resistance. Recent advances in nanotechnology have enabled precise modulation of these immune populations, offering a promising avenue to enhance the efficacy of cancer immunotherapy. Nano-enabled platforms can reprogram TAMs from a pro-tumorigenic M2-like phenotype to an anti-tumorigenic M1-like state, thereby restoring their capacity to phagocytose tumor cells and produce pro-inflammatory cytokines. Concurrently, nanomaterials can enhance DC activation and antigen presentation, promoting robust T-cell priming and adaptive immune responses. Various nanocarriers, including liposomes, polymeric nanoparticles, and inorganic nanostructures, have been engineered to deliver immune modulators, nucleic acids, or tumor antigens selectively to TAMs and DCs within the tumor microenvironment. These strategies have demonstrated synergistic effects when combined with immune checkpoint blockade or cytokine therapy, resulting in improved tumor regression and long-term immunological memory in preclinical models. Despite these promising outcomes, challenges remain regarding nanomaterial biocompatibility, targeted delivery efficiency, and potential off-target immune activation. Ongoing research is focused on optimizing nanoparticle physicochemical properties, surface functionalization, and multi-modal delivery systems to overcome these limitations. This review highlights recent advances in nano-enabled modulation of TAMs and DCs, emphasizing mechanistic insights, therapeutic outcomes, and translational potential. By integrating nanotechnology with immunotherapy, these approaches offer a powerful strategy to overcome tumor immune evasion, paving the way for more effective and personalized cancer treatments.

Keywords:  M2-like phenotype; T-cell priming; dendritic cells; nanoparticle; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/nano16030172
Cancer Immunol Res. 2026 Feb 13.

CLK1 Promotes Myeloid-Derived Suppressor Cell Trafficking and Reprograms the Tumor Microenvironment by activating Hippo/YAP signaling in Colorectal Cancer.

Peisi Li, Yumo Xie, Dawang Zhou, Xuan Li, Qishan Liu, Ziming Li, Xiaoxia Liu, Jinxin Lin, Meijin Huang, Qian Yan, Yanxin Luo, Huichuan Yu, Xiaolin Wang.

Colorectal cancer (CRC) is a highly heterogeneous malignancy characterized by complex interactions between tumor cells and the immune system. The tumor microenvironment (TME) plays a crucial role in CRC progression and response to therapy. However, the mechanisms regulating TME composition remain poorly understood due to the genetic and phenotypic diversity of tumor cells. In this study, we investigated the tumor-intrinsic factors contributing to TME formation and evaluated genotype-based combination strategies to enhance the efficacy of immunotherapy in CRC. Using RNA sequencing, single-cell analysis, and immunohistochemistry, we identified pro-oncogenic proteins associated with low immune activation. Functional studies using in vitro co-culture systems, subcutaneous CRC tumor models, flow cytometry, and immunohistochemistry revealed a role for CLK1 in tumor progression and immunosuppressive TME remodeling. Mechanistically, CLK1 activation led to hyperactivation of the Hippo signaling pathway, promoting nuclear translocation of YAP and subsequent transcriptional upregulation of the chemokine CXCL1. Elevated CLK1 expression correlated with increased infiltration of myeloid-derived suppressor cells (MDSCs) and impaired antitumor immune responses. Knockdown of CLK1 significantly reduced MDSC recruitment and restored CD8+ T-cell activity. Moreover, combined CLK1 knockdown and anti-PD1 therapy enhanced intratumoral CD8+ T-cell infiltration to a greater extent and elicited robust antitumor responses in murine CRC models. Collectively, our findings identify the CLK1-Hippo/YAP-CXCL1 signaling axis as a regulator of immune evasion and TME remodeling in CRC and highlight the potential of therapeutically targeting this axis to improve the efficacy of immune checkpoint blockade.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0766
Crit Rev Oncol Hematol. 2026 Feb 06. pii: S1040-8428(26)00077-6. [Epub ahead of print]220 105190

Molecular heterogeneity of Glioblastoma-associated microglia and macrophages and myeloid-derived suppressor cells: Insights from single-cell omics and therapeutic implications.

Saurav Kumar, Sandeepkumar Sriramanujam, Tae Gyu Oh, Priya Balasubramanian, Dinesh Thotala, Sree Deepthi Muthukrishnan.

  Glioblastoma (GBM) is characterized by a highly immunosuppressive microenvironment that is enriched with myeloid cell populations. Historically, these myeloid cells, particularly GBM-associated microglia/macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs), were considered as pro-tumorigenic due to limitations in genomic technologies. However, advances in single-cell and spatial omics have revolutionized our understanding of the GBM immune landscape, uncovering extensive heterogeneity within the myeloid compartment. Studies utilizing murine models and patient-derived samples have demonstrated that GAMs and MDSCs exist along a spectrum of activation states, with both tumor-promoting and tumor-suppressive roles. These findings challenge the conventional view of myeloid cells in GBM and highlight their dynamic and context-dependent functions. This review summarizes key findings from single-cell and spatial-omics studies utilizing human GBM patient samples and highlighting the discovery of novel myeloid cell subsets, immunomodulatory programs, and tumor-niche specific myeloid subpopulations that have reshaped our understanding of the GBM immune landscape. We discuss how specific subpopulations interact with other cellular components of the tumor microenvironment to support tumor invasion, drive immunosuppression, and contribute to therapeutic resistance. Finally, we discuss therapeutic strategies informed by these insights, including subset-directed myeloid reprogramming, stimulating innate immune signaling and phagocytosis, and rational combinations of myeloid-targeted agents with chimeric antigen receptor (CAR) T-cell and other immune therapies to improve clinical outcomes in GBM.

Keywords:  Glioblastoma; Glioblastoma-associated microglia/macrophages; Immune suppression; Myeloid-derived suppressor cells; Single-cell omics

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105190
Front Pharmacol. 2026 ;17 1745590

Induction of immunogenic cell death by active components of natural products reshaping the tumor microenvironment for enhanced antitumor immunity.

Xiaojie Chen, Haojia Li, Jianfei Chen, Boyang Hou, Zhaokun Tian, Wenyan Qiu, Zhiyong Yu.

   Background: The immunosuppressive tumor microenvironment (TME) is a principal factor limiting the success of current cancer immunotherapies. Immunogenic cell death (ICD), a process whereby dying tumor cells elicit an adaptive immune response through the emission of damage-associated molecular patterns (DAMPs), offers a promising strategy to counteract this limitation. Natural products (NPs) constitute a valuable reservoir of compounds capable of triggering ICD.
Purpose: This review aims to provide a comprehensive overview of ICD inducers derived from NPs, detail their molecular mechanisms of action, and explore their capacity to remodel the immunosuppressive TME.
Methods: We performed a comprehensive literature search in relevant electronic databases to identify studies describing NPs-based components that stimulate characteristic ICD markers, such as surface exposure of calreticulin (CRT), and extracellular release of ATP and high mobility group box 1 (HMGB1).
Results: Active components of NPs were demonstrated to initiate ICD largely via the induction of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS). The consequent emission of DAMPs facilitates dendritic cell-mediated phagocytosis of tumor antigens and the priming of cytotoxic T lymphocytes. Additionally, the inflammatory milieu generated by NPs-induced ICD reprograms the TME by promoting the repolarization of macrophages to an immunostimulatory M1 phenotype and inhibiting the suppressive functions of myeloid-derived suppressor cells (MDSCs).
Conclusion: Inducing ICD with NPs is a viable therapeutic strategy to potentiate anti-tumor immunity. The convergence of NPs-based ICD inducers with nanotechnology-based delivery systems offers a robust platform for the development of innovative combination regimens aimed at improving patient outcomes.

Keywords:  cancer immunotherapy; damage-associated molecular patterns; immunogenic cell death; nanodelivery; natural products; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2026.1745590
Int J Mol Sci. 2026 Feb 03. pii: 1510. [Epub ahead of print]27(3):

Targeting Matrix Stiffness and Mechanotransduction in Breast Cancer: Implications for Emerging Therapies.

Michael Hall, Ozichi Amobi, John Khalaf, Afees John Olanrewaju, Eileen Brantley.

  Breast cancer remains a leading cause of mortality among women worldwide. The inherent heterogeneity in tumors among patients with breast cancer poses a challenge to effective therapeutic management. The extracellular matrix (ECM) is an important structural component of the tumor microenvironment (TME) that regulates cellular behavior. When the ECM adopts a stiff configuration, this coincides with biochemical remodeling in response to biomechanical cues that drive tumor cell invasion, immune evasion, and metastatic spread in breast cancer. Emerging studies suggest that patient ancestry significantly impacts ECM stiffness to contribute to disparities in breast cancer survival. In this review, we discuss recent advances in our understanding of how the tumor ECM orchestrates breast cancer invasion and metastasis through mechanotransduction signaling to promote breast cancer progression. We also discuss ancestry-associated differences in breast ECM architecture and agents targeting mechanotransduction signaling pathways with potential to treat breast cancer and improve patient outcomes. Collectively, this review will highlight the significance of tumor mechanobiology and present emerging therapies that target stiffness-sensitive mechanotransduction pathways. By integrating mechanistic insights with therapeutic innovation, we aim to support the development of ECM-targeted therapies to enable more efficacious treatment of aggressive breast cancer subtypes.

Keywords:  breast cancer; disparities; epithelial-mesenchymal transition; extracellular matrix stiffness; mechanotransduction; metastatic cascade; tumor invasion

DOI:  https://doi.org/10.3390/ijms27031510
Oncol Rep. 2026 Apr;pii: 66. [Epub ahead of print]55(4):

Impact of the intratumoral resident microbiome on the immune microenvironment of malignant tumors (Review).

Han Na Oh, Hoon Hur.

  Advances in cancer research have highlighted the importance of tumor‑intrinsic factors, including tumor type, immune environment, immunogenicity, metabolic demands and the intratumoral microbiome. Together, these factors have reshaped the current understanding of cancer immunity and systemic therapies, particularly targeted treatments and immune checkpoint inhibitors that act on cancer cells, blood vessels and immune cells within the tumor microenvironment (TME). Among these, the presence of bacteria within tumors has emerged as a critical modulator of the TME, influencing tumor progression and antitumor responses across various cancer types. With the rapid expansion of cancer immunotherapies, advanced detection and sequencing technologies are increasingly applied to elucidate interactions between intratumoral microbiota and immune cells. The present review focuses on the mechanisms by which tumor bacteria modulate immune responses, supported by validations from in vitro and in vivo studies. The potential of intratumoral microbiota as biomarkers for prognosis and immunotherapy response is also discussed, alongside emerging biotechnological tools for microbiota profiling. By examining the dual roles of intratumoral microbiota in cancer biology, the current review provides a comprehensive overview of their implications and practical applications in cancer‑related research.

Keywords:  biotechnological tools; immune microenvironment; immunotherapy; intratumoral microbiome; multi-omics approaches; tumor bacteria

DOI:  https://doi.org/10.3892/or.2026.9071
Cancer Res. 2026 Feb 13.

LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.

Zhihong Luo, Kangdi Li, You Yu, Yi Liu, Hong Weng, Xian-Tao Zeng, Yi Zheng, Wenhua Li.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and often undergo metabolic reprogramming. Metabolic shifts within CAFs can influence cancer cell behavior. In this study, we revealed that the loss of lactate dehydrogenase B (LDHB) in CAFs drives a metabolic shift that significantly enhances breast cancer metastasis. LDHB loss in CAFs drove a shift towards an inflammatory fibroblast phenotype. Mechanistically, LDHB deficiency led to lactate accumulation, which disrupted the interaction between dual specificity phosphatase 16 (DUSP16) and p38, causing sustained p38 activation. Persistent p38 signaling reprogrammed CAFs into an inflammatory phenotype characterized by abundant secretion of the chemokine CXCL8, which in turn enhanced metastasis of breast cancer cells. In summary, these findings identify LDHB as a key metabolic regulator in CAFs and provide insights into how metabolic reprogramming promotes the inflammatory, pro-metastatic phenotype of CAFs, highlighting activating LDHB as a potential strategy for limiting cancer metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2792
Acta Biochim Biophys Sin (Shanghai). 2026 Feb 11.

CAR-macrophages: a new chapter in cancer immunotherapy.

Xucai Tang, Qian Xiao.

  Chimeric antigen receptor T (CAR-T) cell therapy achieves remarkable success in hematological cancers, but its efficacy is severely limited in solid tumors by formidable obstacles including physical barriers, the highly immunosuppressive tumor microenvironment (TME), and antigen escape. To address these persistent challenges, chimeric antigen receptor-macrophage (CAR-M) therapy emerges as a promising alternative, leveraging intrinsic advantages of macrophages like unparalleled tumor infiltration, powerful phagocytosis, and high plasticity. The evolution of CAR-M is primarily defined by the intracellular signaling domain. CAR-M exerts its anti-tumor effects through multifaceted mechanisms, including direct enhanced phagocytosis and tumor cell killing, TME remodeling by repolarizing to a pro-inflammatory M1-like phenotype, releasing anti-tumor effectors, and degrading the extracellular matrix (ECM), and the activation of adaptive immunity via efficient antigen presentation. Despite its promise, CAR-M faces hurdles such as TME physical barriers and the potential for M2-like re-education. Current optimization strategies focus on enhancing tumor infiltration, overcoming immunosuppression with "armored" CAR-Ms, and improving safety with suicide switches. Encouraging pre-clinical data accelerates CAR-M into early-phase clinical trials for solid tumors, and the platform's utility is also being explored beyond oncology in infectious, autoimmune, and neurodegenerative diseases.

Keywords:  CAR-macrophages (CAR-Ms); adoptive cell therapy; solid tumors; tumor microenvironment remodeling

DOI:  https://doi.org/10.3724/abbs.2026017
Int J Mol Sci. 2026 Jan 28. pii: 1292. [Epub ahead of print]27(3):

Targeting Macrophages in Immunotherapy: The Ascent of CAR-Macrophages.

Vinod Nadella, Anu Sharma.

  Chimeric antigen receptor (CAR)-engineered immune cell therapies have revolutionized cancer treatment, with CAR-T cells demonstrating remarkable efficacy against hematological malignancies. However, the effectiveness of CAR-T and other lymphocyte-based therapies against solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment and poor infiltration of effector cells. Recently, CAR-macrophage (CAR-M) immunotherapy has emerged as a promising strategy to overcome these barriers. Leveraging the innate tumor-homing ability, phagocytic function, and antigen-presenting capacity of macrophages, CAR-M therapies offer unique advantages for targeting solid tumors. This review provides a comprehensive overview of the development and current state of CAR-Macrophage immunotherapy, including advances in CAR design and macrophage engineering, preclinical and clinical progress, and mechanistic insights into their anti-tumor activity. The review critically examined both the benefits and limitations of CAR-M approaches, addressing persistent challenges such as cell sourcing, durability, and safety, while also exploring innovative strategies to enhance therapeutic efficacy. Finally, future perspectives and the potential clinical impact of CAR-macrophage therapies were outlined, underscoring their emerging role in the evolving landscape of cancer immunotherapy.

Keywords:  cancer; cell therapy engineering; chimeric antigen receptor; immunotherapy; macrophages; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27031292
Transl Cancer Res. 2026 Jan 31. 15(1): 45

Association of METTL14 expression with prognosis and immunotherapy in breast cancer.

Junbo Hu, Zhen Wang, Yanju Lu, Zhen Wei, Lindan Dong, Yuxia Li, Honglin Yan, Na Tang.

   Background: Methyltransferase-like 14 (METTL14) is recognized as a key factor in the advancement and progression of breast cancer (BC). While its involvement in this context is acknowledged, many aspects of METTL14's functions remain unclear. We aimed to explore the function and potential mechanism of METTL14 in BC.
Methods: The level of METTL14 in BC cell lines and tissues was evaluated using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting methods. The cell counting kit-8 (CCK-8) assay, wound healing assay, and transwell chamber assay were employed to investigate the biological functions of METTL14 in BC. The relationship between immune characteristics and METTL14 was analyzed using the Tumor Immune Estimation Resource (TIMER) and Tumor-Immune System Interaction Database (TISIDB). The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapy response of BC patients. Multiplex immunofluorescence (mIF) was used to evaluate the expression of eight candidate markers of immune cell subsets and checkpoints in BC samples. Furthermore, a Kaplan-Meier survival analysis was performed to assess the prognostic significance of METTL14 in BC.
Results: Our study revealed a significant downregulation of METTL14 in BC tissues. The reduced expression of METTL14 was found to be associated with tumor progression, unfavorable recurrence-free survival (RFS) outcomes, and advanced tumor stages. Furthermore, METTL14 expression exhibited a positive correlation with the abundance of CD8+ T cells, CD4+ T cells, macrophages, and mast cells, while a negative correlation was observed with the abundance of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and follicular helper T cells, as determined through immune analysis. METTL14 downregulation is associated with an immunosuppressive tumor microenvironment (TME), potentially through the upregulation of certain immunosuppressive factors. Results from mIF confirmed that low METTL14 expression correlates with high programmed death-1 (PD-1) expression. The analysis using the TIDE algorithm indicated that METTL14 expression was primarily negatively associated with the response to immunotherapy.
Conclusions: METTL14 demonstrates significant predictive value regarding prognosis in BC. The METTL14 has the potential to serve as a predictive biomarker and a promising target for immunotherapy.

Keywords:  Breast cancer (BC); CD4+ T cells; immunotherapy; methyltransferase-like 14 (METTL14); tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/tcr-2025-1331
Biochim Biophys Acta Rev Cancer. 2026 Feb 09. pii: S0304-419X(26)00026-0. [Epub ahead of print]1881(2): 189554

Emerging perspectives on metabolic reprogramming in the microenvironment of ovarian cancer metastasis.

Jing Ma, Sally K Y To, Xinyu Zhang, Weiyang Zhao, Peng Zhang, Alice S T Wong.

  Ovarian cancer (OC) is one of the most lethal malignancies in females, mainly due to the aggressive metastasis at the late stage and the unsatisfactory of current therapies. OC cells exhibit a special metastatic behavior compared to other common epithelial tumors, primarily spreading within the peritoneal cavity. Due to the complexity of tumor microenvironment, physical factors induce significant metabolic changes in OC cells, thereby enhancing their metastatic ability. Key cellular components, such as cancer-associated fibroblasts and adipocytes, act synergistically to support metastasis through metabolic interactions. Recent efforts in tumor immunometabolism showed that metabolic reprogramming of immune cells can also significantly impact metastatic progression. Moreover, the microbiome and cellular senescence are emerging as important factors that alter the metabolic landscape. This review provides a systematic review of metabolic reprogramming in the OC microenvironment and highlights the most recent clinical trials targeting metabolic pathways. By increasing our understanding of these metabolic interactions, we can develop innovative metabolism-targeting interventions for this devastating gynecological malignancy.

Keywords:  Immunometabolism; Metabolic crosstalk; Metabolic reprogramming; Ovarian cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189554
Cancer Sci. 2026 Feb 13.

Mitochondrial Transfer in the Tumor Microenvironment.

Ryo Omae, Takamasa Ishino, Yosuke Togashi.

  Mitochondria are not merely energy-producing organelles but also regulate metabolism, apoptosis, and inflammation. Recent studies have reported that mitochondria can be transferred between cells, and accumulating evidence suggests that this phenomenon is functionally relevant in the tumor context. Mitochondrial transfer is mediated by multiple routes such as tunneling nanotubes and extracellular vesicles. These pathways are regulated by Miro1/2, connexin 43, ICAM-1, VCAM-1, and intracellular reactive oxygen species. Within the tumor microenvironment, mitochondrial transfer from surrounding cells to tumor cells may serve as a mechanism by which tumor cells adapt to hostile metabolic conditions and evade therapeutic pressure. Furthermore, mitochondrial transfer from tumor cells to T cells in the tumor microenvironment reportedly impairs antitumor immunity. Based on these findings, novel therapeutic strategies targeting mitochondrial transfer are under investigation. Future challenges include the development of specific and safe methods to manipulate mitochondrial transfer in vivo. Understanding mitochondrial transfer and its regulation may offer new avenues to overcome resistance and improve cancer outcomes.

Keywords:  antitumor immunity; cell‐to‐cell interaction; mitochondria; mitochondrial transfer; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70342