bims-flamet 2026-02-22 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–02–22
25 papers selected by
Peio Azcoaga, Biodonostia HRI

A Folate Receptor β-Targeted TLR7 Agonist Significantly Augments Checkpoint Inhibitor Potencies by Reprogramming Tumor-Associated Macrophages and Myeloid-Derived Suppressor Cells.
Regulating the regulators via targeting CD38 in the tumor microenvironment.
Unveiling the tumor microenvironment in colorectal cancer therapeutic resistance.
The role of tumor-associated macrophages in cancer development and their significance as prognostic markers.
SPP1 as a central mediator in the tumor microenvironment: Orchestrating cellular crosstalk, immune evasion, and therapy resistance.
Therapeutic targeting of toll-like receptor pathways in tumor-associated macrophages.
Emerging roles of IL4I1 in regulating tumor immunity and ferroptosis.
Metabolic crosstalk between cancer and stromal cells: Implications for precision oncology.
Striking a nerve: Sensory neurons orchestrate ECM remodeling and immune exclusion in TNBC.
Metabolic reprogramming orchestrates an immunosuppressive microenvironment in anaplastic thyroid cancer: mechanisms and clinical perspectives.
Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.
M1 macrophage membrane-engineered PLGA nanoparticles reprogram M2 tumor-associated macrophages to enhance anti-tumor immunity in breast cancer.
Mechanisms of therapy resistance in the tumor microenvironment: Insights from antibody array-based cytokine profiling.
Pleiotropic mechanisms of cancer-associated fibroblast-mediated resistance in hepatocellular carcinoma: emerging therapeutic vulnerabilities and targeting strategies.
Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.
From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy.
Pleiotropic and multicellular roles of lymphotoxin beta receptor in solid tumor immunity and therapeutic targeting.
Antibody-nanoparticle conjugates for precision targeting of immunosuppressive tumor microenvironment.
Myeloid-derived suppressor cells and regulatory T cells in colorectal cancer: a synergistic immunosuppressive axis and emerging therapeutic opportunities.
Targeting MAFB potentiates immune checkpoint inhibitor efficacy by reprogramming tumor-associated macrophages to an M1-like phenotype in colorectal cancer.
Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.
Current state of CAR-T cell therapies for solid tumors.
Metabolism in Tumour-Induced Bone Disease.
The insider's perspective: The intracellular complosome and immune cell dynamics in cancer.
Reprogramming the tumor microenvironment: methylmalonic acid at the intersection of ccRCC metabolism and macrophage polarization.

J Med Chem. 2026 Feb 17.

A Folate Receptor β-Targeted TLR7 Agonist Significantly Augments Checkpoint Inhibitor Potencies by Reprogramming Tumor-Associated Macrophages and Myeloid-Derived Suppressor Cells.

John V Napoleon, Rami Alfar, Fenghua Zhang, Emily A Raine, Taylor A Wolt, Philip S Low.

Although immune checkpoint inhibition has emerged as a promising treatment for many solid tumors, infiltrating immune cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), can limit their potencies. To address this issue, we used folic acid to target a Toll-like receptor 7 (TLR7) agonist to folate receptor β (FRβ) expressing TAMs and MDSCs, with the anticipation that repolarization of these myeloid cells to tumoricidal phenotypes might restore the intrinsic potencies of checkpoint inhibitors. We demonstrate that this folate-TLR7 conjugate can not only reprogram FRβ-expressing myeloid cells in the tumor microenvironment (TME) but can also induce a global shift in the TME to an inflammatory state. We then demonstrate that TME repolarization significantly enhances the potencies of both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors in multiple tumor models and conclude that the reprogramming of TAMs/MDSCs to a tumoricidal phenotype can significantly augment the potencies of checkpoint inhibitors without causing toxicity to healthy tissues.

DOI: https://doi.org/10.1021/acs.jmedchem.5c03277
Front Immunol. 2026 ;17 1745988

Regulating the regulators via targeting CD38 in the tumor microenvironment.

Navnita Dutta, Nabanita Halder, Eduardo Nunes Chini, Sungjune Kim, Alak Manna.

  The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Among the central regulators of immune suppression, CD38, a multifunctional ectoenzyme and surface glycoprotein, has emerged as a pivotal orchestrator. CD38 is abundantly expressed on regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), where it enhances survival, metabolic fitness, and suppressive activity. Invariant natural killer T (iNKT) cells, which can either promote or suppress antitumor immunity, also express CD38 upon activation, suggesting a role for CD38 in directing their context-dependent fate within the TME. Mechanistically, CD38 regulates immune suppression through NAD+ hydrolysis, calcium signaling, and promotion of fatty acid oxidation (FAO) while impairing effector T-cell glycolysis and mitochondrial fitness under chronic hypoxia-conditions that favor exhaustion rather than enhanced cytotoxicity. By depleting extracellular NAD+, CD38 diminishes glycolysis and mitochondrial oxidative phosphorylation in effector T cells, while sustaining regulatory cell persistence through FAO. Its enzymatic products, cyclic ADP-ribose (cADPR) and NAADP, further mobilize calcium fluxes that reinforce suppressive function. CD38 also integrates with hypoxia-driven pathways; in CD38+ Bregs, stabilization of HIF-1α and induction of FAO-related genes such as CPT1A and PPARα/γ promote angiogenesis, immune-evasion, and therapeutic resistance. Therapeutically, targeting CD38 with monoclonal-antibodies, small-molecule inhibitors, or combinations with checkpoint blockade and macrophage-reprogramming agents has shown promise. Such interventions reverse immune suppression, restore effector T cell activity, and enhance tumor responsiveness to immunotherapy. In summary, CD38 functions as both a metabolic regulator and an immunologic checkpoint, coordinating suppressive networks and shaping iNKT cell fate. These multifaceted roles position CD38 as a transformative target for next-generation immunotherapies.

Keywords:  Breg; CD38; NAD; metabolism; tumor micro environment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1745988
Front Cell Dev Biol. 2025 ;13 1753180

Unveiling the tumor microenvironment in colorectal cancer therapeutic resistance.

Jiyu Han, Weitian Liang, Kai Li.

  Therapeutic resistance remains a major barrier to effective treatment in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a pivotal role in modulating responses to chemotherapy, immunotherapy, and targeted therapies. This review synthesizes current evidence on how cellular and non-cellular TME components contribute to resistance mechanisms in CRC. Key immune cells, including T cells, macrophages, neutrophils, natural killer cells, dendritic cells, and myeloid-derived suppressor cells, orchestrate immunosuppressive networks that impair drug efficacy. For instance, regulatory T cells and M2-polarized macrophages promote chemoresistance via cytokine secretion and metabolic reprogramming, while neutrophils and myeloid-derived suppressor cells hinder immune checkpoint blockade through extracellular trap formation and T-cell exhaustion. Non-cellular elements, such as extracellular matrix remodeling, hypoxia-induced metabolic shifts, and dysregulated cytokines like IL-6 and TGF-β, further exacerbate resistance by fostering epithelial-mesenchymal transition and angiogenesis. Tables highlight specific molecular axes and therapeutic implications. By elucidating these interactions, this article underscores the potential of TME-targeted strategies, such as macrophage reprogramming, cytokine inhibition, and combination therapies, to overcome resistance and improve clinical outcomes in CRC patients. Future research should prioritize integrating TME biomarkers for personalized treatment approaches.

Keywords:  TIME; TME; chemotherapy; colorectal cancer; drug resistance; immunotherapy; targeted therapy

DOI:  https://doi.org/10.3389/fcell.2025.1753180
Clin Exp Med. 2026 Feb 16. 26(1): 155

The role of tumor-associated macrophages in cancer development and their significance as prognostic markers.

Arash Salmaninejad, Sepideh Mehrpour Layeghi, Zeinab Falakian, Parisa Safari Foroushani, Shahin Golestani, Farzad Pourghazi, Sepehr Kobravi, Meysam Yousefi.

  Macrophages are a diverse group of immune cells which have key roles in immune defense, tumor homeostasis, and wound repair. During the last two decades, the role of macrophages as one of the most abundant tumor-infiltrating stromal cells has gradually emerged. The normal function of these tumor-associated macrophages (TAMs) in tumor microenvironment (TME) is to suppress tumor cells through triggering both direct cell cytotoxicity and antibody-mediated immune response. However, they have also been implicated in the progression of cancers. Tumor cells produce chemokines that polarize macrophages into tumor-promoting TAMs. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. High plasticity of TAMs makes it feasible to regulate their polarization and adjust the balance between the anti-tumor TAMs and those with pro-tumor phenotypes. In this review, we aim to provide an overview about the origin and polarization of TAMs and their significance as biomarkers for the prediction and prognostication of various cancers.

Keywords:  Cancer development; Cancer prognosis; Macrophage polarization; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1007/s10238-026-02055-0
Biochim Biophys Acta Rev Cancer. 2026 Feb 13. pii: S0304-419X(26)00027-2. [Epub ahead of print]1881(2): 189555

SPP1 as a central mediator in the tumor microenvironment: Orchestrating cellular crosstalk, immune evasion, and therapy resistance.

Linhong Wang, Yachen Cheng, Jialu Li, Rulan Liao, Xiaohui Gao, Renle Du.

  Secreted phosphoprotein-1 (SPP1) is a multifaceted glycoprotein that extends beyond its role as a mere component of the extracellular matrix, functioning instead as a pivotal signaling hub within the tumor microenvironment (TME). This review synthesizes current evidence regarding how SPP1 orchestrates a complex cellular network by mediating bidirectional crosstalk between cancer cells and key stromal components including cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and lymphocytes. We elucidate how these interactions drive TME reprogramming, facilitating processes such as extracellular matrix remodeling, angiogenesis, immune evasion, and the establishment of therapeutic resistance to both chemotherapy and immunotherapy. Furthermore, we assess emerging therapeutic strategies targeting SPP1 such as aptamers and antibodies, highlighting their preclinical efficacy alongside the translational challenges that must be addressed. Ultimately, targeting the SPP1-mediated network represents a promising approach for dismantling the pro-tumorigenic TME and enhancing cancer treatment outcomes.

Keywords:  SPP1; Tumor microenvironment; Tumor-associated fibroblasts; Tumor-associated macrophages; Tumor-infiltrating lymphocytes; cancer therapy

DOI:  https://doi.org/10.1016/j.bbcan.2026.189555
Cytokine Growth Factor Rev. 2026 Feb 13. pii: S1359-6101(26)00019-5. [Epub ahead of print]88 138-151

Therapeutic targeting of toll-like receptor pathways in tumor-associated macrophages.

Lei Wang, Yinghua Li, Zehua He, Zhaoshuai Chen, Wencan Zhang, Chengsheng Wu, Liqiong Xue, Xu Cao.

  Tumor-associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME), shaping immune suppression, tumor progression, and therapeutic resistance. Toll-like receptors (TLRs) orchestrate innate immune activation and represent a compelling axis for reprogramming TAMs toward antitumor states. However, the context-dependent nature of TLR signaling, combined with metabolic and tolerogenic constraints in the TME, presents substantial translational barriers. Nevertheless, recent advances including chimeric antigen receptor macrophage (CAR-M) and antibody-TLR agonist conjugates offer new pathways to harness TLR signaling with improved precision and safety. This review summarizes the molecular foundations of TLR signaling in macrophages, dissects the bidirectional consequences of TLR activation within tumors, evaluates current therapeutic platforms, and outlines a translational roadmap to guide the clinical development of TLR-based TAM modulation.

Keywords:  (TAMs); Cancer Immunotherapy; Chimeric antigen; Innate immune system; Receptor macrophage (CAR-M); Toll-like receptors (TLRs); Tumor microenvironment (TME); Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.cytogfr.2026.02.001
Biochim Biophys Acta Rev Cancer. 2026 Feb 12. pii: S0304-419X(26)00025-9. [Epub ahead of print]1881(2): 189553

Emerging roles of IL4I1 in regulating tumor immunity and ferroptosis.

Yiming Hu, Yuhan Jiang, Yunfan Du, Yue Zheng, Xiaojun Xia.

  The tumor microenvironment (TME) plays a crucial role in driving tumor progression and facilitating immune evasion, acting as a complex network in which immune cells, stromal components, and tumor cells interact dynamically. Among the various factors influencing the TME, interleukin-4-induced protein 1 (IL4I1) has emerged as a key regulator of immune suppression and tumor growth. Through its enzymatic activity, IL4I1 metabolizes aromatic amino acids into a plethora of bioactive metabolites that inhibit ferroptosis and activate the aryl hydrocarbon receptor (AHR) signaling, thereby promoting anti-inflammatory macrophage polarization, regulatory T cell differentiation, and inhibition of effector T lymphocytes, ultimately inducing immune tolerance. These processes facilitate immune escape of cancer cells within the TME, where IL4I1 expression is often elevated and associated with poor prognosis. This review highlights the multifaceted role of IL4I1 within the TME, focusing on its immune regulatory function and anti-ferroptotic function. By exploring IL4I1's function in regulating different immune cell subsets and new role in promoting tumor resistance to ferroptosis, we discuss the major unanswered questions about how IL4I1 regulates tumor immunity, and propose the significance of developing targeted therapies that inhibit IL4I1, potentially in combination with inhibitors targeting IDO1 or immune checkpoints, to enhance antitumor immunity and improve clinical outcomes of cancer patients.

Keywords:  AHR; Ferroptosis; IL4I1; Immunosuppression; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2026.189553
Surg Oncol. 2026 Feb 12. pii: S0960-7404(26)00017-4. [Epub ahead of print]65 102366

Metabolic crosstalk between cancer and stromal cells: Implications for precision oncology.

Wanwan Yang, Yuwen Ding, Hongzhan Tian.

  Metabolic reprogramming is a hallmark of cancer that extends beyond the boundaries of individual tumor cells to encompass a complex metabolic network within the tumor microenvironment (TME). Cancer cells engage in dynamic metabolic crosstalk with stromal components including fibroblasts, immune cells, endothelial cells, and adipocytes through the exchange of metabolites, signaling molecules, and extracellular vesicles. These interactions coordinate energy production, redox homeostasis, and biosynthetic pathways that sustain tumor growth, angiogenesis, immune evasion, and therapeutic resistance. Cancer-associated fibroblasts (CAFs) supply lactate, amino acids, and lipids that fuel tumor anabolism; immune cells undergo metabolic suppression under nutrient competition and acidic stress; endothelial and adipose cells contribute to angiogenesis and metastatic adaptation through glycolysis and lipid transfer. This metabolic dialogue is governed by key signaling pathways (HIF-1α, mTOR, AMPK, c-Myc, PPAR, NRF2) and modulated by epigenetic mechanisms linking metabolic flux to gene expression. Understanding these multilayered communications provides novel insights into the cooperative and competitive nature of tumor metabolism. Emerging technologies such as spatial metabolomics and single-cell multi-omics are now enabling the identification of patient-specific metabolic dependencies. Targeting metabolic symbiosis rather than isolated pathways represents a promising direction for precision oncology, offering opportunities to disrupt tumor stroma cooperation, overcome therapeutic resistance, and personalize metabolism-based interventions.

Keywords:  Cancer-associated fibroblasts; Metabolic crosstalk; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.suronc.2026.102366
Cell. 2026 Feb 19. pii: S0092-8674(26)00107-8. [Epub ahead of print]189(4): 993-994

Striking a nerve: Sensory neurons orchestrate ECM remodeling and immune exclusion in TNBC.

Debra Barki, Neta Eilat, Ruth Scherz-Shouval.

The tumor microenvironment drives cancer progression, yet neural contributions remain underexplored. Zhang et al. unravel a signaling circuit involving cancer cells, sensory neurons, and cancer-associated fibroblasts that promotes desmoplasia and excludes cytotoxic T cells, positioning the neuron-fibroblast axis as a therapeutic vulnerability and potential predictor of immunotherapy response.

DOI: https://doi.org/10.1016/j.cell.2026.01.020
Front Immunol. 2026 ;17 1699202

Metabolic reprogramming orchestrates an immunosuppressive microenvironment in anaplastic thyroid cancer: mechanisms and clinical perspectives.

Jinkun Xia, Baowei Zhai.

  Anaplastic Thyroid Carcinoma (ATC) represents one of the most aggressive and lethal human malignancies, characterized by rapid progression, profound therapy resistance, and a dismal prognosis. Recent advances have underscored metabolic reprogramming as a cornerstone of ATC pathogenesis, enabling tumor cells to adapt to a hostile microenvironment, sustain proliferation, and evade immune destruction. This review systematically delineates how metabolic alterations in ATC-spanning enhanced glycolysis, deregulated lipid metabolism, and aberrant amino acid utilization-orchestrate a profoundly immunosuppressive tumor immune microenvironment (TIME). We explore the mechanistic links between tumor metabolism and immune dysfunction, including nutrient competition-induced energy deficits in effector immune cells, accumulation of immunosuppressive metabolites, and metabolic regulation of immune checkpoint expression. Furthermore, we discuss the impact of metabolic crosstalk on immune cell phenotypes, fostering the recruitment and polarization of pro-tumorigenic immune populations such as M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells. Clinically, we highlight the therapeutic promise of targeting key metabolic nodes and review emerging combination strategies that integrate metabolic inhibitors with immune checkpoint blockade to overcome resistance and enhance antitumor immunity. By synthesizing foundational insights with cutting-edge preclinical and clinical evidence, this review aims to provide a cohesive mechanistic framework and identify novel, metabolism-based therapeutic vulnerabilities for precision immunotherapy in ATC.

Keywords:  anaplastic thyroid carcinoma; immune evasion; immune microenvironment; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2026.1699202
iScience. 2026 Feb 20. 29(2): 114788

Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.

Lingyu Ding, Zhen Li, Jing Yue, Liqing Qiu, Zhifeng Tian, Hongfang Zhang.

  Tumor metastasis represents a lethal event for patients due to the lack of effective treatments. Compared with primary tumors, the components of the tumor microenvironment (TME) of metastatic tumors are different. Tumor cells alone are unable to metastasize. Cancer-associated fibroblasts (CAFs), as one major component of TME, drive tumor metastasis. In metastatic lesions, the proportion of CAFs is significantly higher and is spatially close to tumor cells with high metastatic potential. CAFs themselves are resistant to chemoradiotherapy and have strong invasive ability based on their major role in degrading the extracellular matrix (ECM). Furthermore, CAFs determined the organs to which tumor cells metastasize. By interaction with tumor cells, CAFs were activated, transdifferentiated, and in turn enhanced the invasive ability of tumor cells. Tumor cells also promoted the infiltration of CAFs in tumor tissues, allowing them to establish a pre-metastatic microenvironment. In this review, we have deeply analyzed the association of CAFs and tumor metastasis from the perspectives of exosomes, metabolic reprogramming, suppression of anti-tumor immunity, and epigenetic modification. We also discussed the future perspectives of CAFs-based anti-metastasis strategies. This information may deepen our understanding of CAFs-initiated tumor metastasis and shed novel insight into the development of anti-metastasis therapies.

Keywords:  Cancer; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.114788
J Mater Sci Mater Med. 2026 Feb 20.

M1 macrophage membrane-engineered PLGA nanoparticles reprogram M2 tumor-associated macrophages to enhance anti-tumor immunity in breast cancer.

Asal Katebi, Farhad Riazi-Rad, Fatemeh Ahangari, Soheila Ajdary.

Nanoparticles (NPs) are used as a suitable delivery system in cancer immunotherapy. Coating NPs with cell membranes can improve their therapeutic efficacy. Tumor-associated macrophages (TAMs) with a dominant phenotype of M2 and anti-inflammatory properties are found within the tumor microenvironment and contribute to tumor progression. Reprogramming TAMs toward a pro-inflammatory M1 phenotype can be a suitable approach to alter the tumor microenvironment and improve treatment outcomes. In this study, we synthesized poly(lactic-co-glycolic acid) (PLGA) NPs loaded with a TLR7/8 agonist (R848) and coated with M1 macrophage cell membranes (CM1), along with a cyclic dinucleotide (CDN) agonist (PLGA-CM1-CDN-R848 NPs), and their ability to reprogram M2-like macrophages was investigated using an in vitro model. PLGA-CM1-CDN-R848 NPs were preferentially taken up by M2-like macrophages and efficiently stimulated the pro-inflammatory cytokines (IL-6, TNF-α, and iNOS) as well as the STING pathway (IFN-β). The reprogrammed macrophages induced apoptosis and cell cycle arrest (G0/G1 and G2/M phases) in 4T1 breast cancer cells. In conclusion, the PLGA-CM1-CDN-R848 NPs formulation represents a promising strategy for breast cancer immunotherapy by targeting M2 TAMs within the TME and reprogramming them toward the M1 phenotype.

DOI: https://doi.org/10.1007/s10856-026-07017-2
Drug Resist Updat. 2026 Feb 13. pii: S1368-7646(26)00029-4. [Epub ahead of print]86 101378

Mechanisms of therapy resistance in the tumor microenvironment: Insights from antibody array-based cytokine profiling.

Rochelle Wickramasekara, Valerie Jones, Yating Zhao, Shuhong Luo, Guogui Sun, Ruo-Pan Huang.

   BACKGROUND: Therapy resistance remains a major obstacle in the treatment of solid tumors and accounts for most cancer-related deaths. While tumor-intrinsic mechanisms have been well-studied, the tumor microenvironment (TME) is now recognized as a major driver of resistance through non-genetic, cell-extrinsic signaling. Stromal and immune cells-including fibroblasts, macrophages, endothelial cells, and regulatory immune cells-interact with cancer cells via cytokine signaling, direct contact, and extracellular matrix (ECM) remodeling to promote survival, immune evasion, and therapeutic adaptation.
OBJECTIVE: This review examines cytokine-mediated signaling mechanisms within the TME that contribute to resistance to chemotherapy, targeted therapy, radiotherapy, and immunotherapy, drawing on studies with a specific focus on antibody array-based multiplex proteomic profiling.
RESULTS: Across multiple tumor types, molecular profiling studies have identified recurrent cytokine and growth factor signaling programs that drive therapy resistance through paracrine and autocrine mechanisms. Key pathways include IL-6/STAT3, CXCL12/CXCR4, and HGF/c-MET among others, through which stromal and immune cells support tumor survival, immune suppression, and therapy evasion. These findings demonstrate that cytokine-mediated resistance mechanisms differ across therapeutic modalities and cellular contexts. Clinical studies targeting these pathways further illustrate how biological context and pathway redundancy influence therapeutic response.
CONCLUSION: Cytokine-driven signaling within the TME plays a central role in therapy resistance. Protein profiling studies have contributed mechanistic insight into these interactions and helped define resistance-associated pathways across treatment settings. Ongoing clinical studies will determine how targeting these pathways can be most effectively applied to improve patient outcomes.

Keywords:  Antibody array; Cancer therapy resistance; Cytokines; Immune suppression; Immunotherapy resistance; Multiplex; Proteomic array; Proteomics; Stromal cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2026.101378
Cancer Gene Ther. 2026 Feb 14.

Pleiotropic mechanisms of cancer-associated fibroblast-mediated resistance in hepatocellular carcinoma: emerging therapeutic vulnerabilities and targeting strategies.

Wei Xie, Jingjing Fang, Zhen Wang, Xia Li, Juan Du, Changquan Ling.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world, with therapy resistance posing a substantial obstacle to enhancing patient outcomes. Cancer-associated fibroblasts (CAFs), the predominant stromal cells within the tumor microenvironment (TME), have been identified as pivotal contributors to HCC progression and therapeutic resistance. CAFs have direct or indirect interactions with cancer cells, leading to immune evasion and drug resistance. This review mostly concentrates on the role of CAFs in HCC, particularly how CAFs influence chemotherapy, targeted therapy, and immunotherapy. Additionally, it explores synergistic therapeutic strategies targeting CAFs. It has been found that targeting CAFs or disrupting their interactions with other cells offers promising avenues for dealing with drug resistance and improving the effectiveness of therapies in HCC.

DOI: https://doi.org/10.1038/s41417-026-01007-w
Int J Biol Sci. 2026 ;22(4): 1950-1973

Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.

Jiaqi Ai, Yiheng Du, Qianqian Xue, Wenbei Peng, Qiong Zhou.

  In recent years, a growing number of evidence suggests that cancer is a metabolic disease. Metabolic reprogramming is a hallmark of the TME, where various nutrients, including glucose, lipids, and amino acids, play key roles in regulating tumor development by acting on both tumor cells and immune cells. T cells are the core mediators of anti-tumor immunity. Especially CD8+ T cells are considered the primary immune cells involved in the anti-tumor immune response. Upon stimulation by tumor antigens and other immune cells, CD8+ T cells undergo metabolic reprogramming through signaling pathways. Metabolites or metabolic checkpoints induce epigenetic changes in key genes, altering the differentiation and effector function of CD8+ T cells. This review first elaborates on the anti-tumor functional characteristics and metabolic profiles of CD8+ T cells at different stages of differentiation in the TME. Then we focus on the roles of key metabolites and metabolic checkpoints in shaping CD8+ T cell differentiation, functionality, and immune responses, specifically through glucose, lipid, and amino acid metabolism. Finally, we discuss the reasons for heterogeneity in the effects of metabolic checkpoints on CD8+ T cells and explore potential clinical applications of metabolic checkpoints in treatment. Understanding the correlation between CD8+ T cell metabolism and anti-tumor immunotherapy may facilitate the development of new strategies to enhance the efficacy of CD8+ T cell-based cancer treatments.

Keywords:  CD8+ T cell; cancer; checkpoint; immunotherapy; metabolism

DOI:  https://doi.org/10.7150/ijbs.125206
Int Immunopharmacol. 2026 Feb 17. pii: S1567-5769(26)00217-1. [Epub ahead of print]174 116373

From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy.

Ying Wang, Yu Yu, Siyu Wang, Jiangyong Qu, Yizhe Song.

  Natural killer (NK) cells are pivotal effector cells of the innate immune system. Their capacity to recognize and eliminate malignant cells without requiring antigen priming has attracted considerable interest in tumor immunotherapy. While NK cell therapy has shown relatively consistent clinical activity across various hematologic malignancies, its efficacy in solid tumors remains highly variable, posing significant challenges for clinical translation. This review summarizes the biological characteristics and antitumor mechanisms of NK cells. Based on published clinical evidence, it describes and synthesizes the heterogeneity in therapeutic efficacy across both solid tumors-including breast cancer (BC), ovarian cancer (OC), and melanoma (MEL)-and hematologic malignancies. The findings indicate that NK cell efficacy heterogeneity arises primarily from multiple factors: immunosuppression within the tumor microenvironment (TME), inadequate tumor infiltration capacity, heterogeneity in target antigen expression, and inhibitory receptor signaling. In addition, product-related attributes-including cell source, genetic engineering strategies, ex vivo expansion protocols, pretreatment regimens, and dosage-substantially influence therapeutic outcomes. Moving forward, the development of NK cell immunotherapy should focus on mechanism-informed patient selection and the rational design of combination therapy to facilitate sustained translation into precision oncology practice.

Keywords:  CAR-NK cells; Hematological malignancies; Immunotherapy; Natural killer cells; Solid tumors

DOI:  https://doi.org/10.1016/j.intimp.2026.116373
Front Immunol. 2026 ;17 1693507

Pleiotropic and multicellular roles of lymphotoxin beta receptor in solid tumor immunity and therapeutic targeting.

Anshu, Nair Shantikumar V, Roy Sreeja.

  Immunotherapy has transformed the treatment landscape of several malignancies, yet solid tumors such as pancreatic ductal adenocarcinoma (PDAC), glioblastoma multiforme (GBM), and triple-negative breast cancer (TNBC) remain largely resistant due to poor immune infiltration, immunosuppressive tumor microenvironments (TMEs) and, the limited success of T cell-centric strategies. The lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor (TNF) receptor superfamily, is broadly expressed on stromal, endothelial, and myeloid cells within the TME and signals through both canonical and non-canonical NF-κB pathways. Depending on context and activation mode, LTβR can drive either tumor progression or anti-tumor immunity. While persistent LTβR signaling supports immunosuppressive macrophage phenotypes and promotes tumor growth in hepatocellular carcinoma, preclinical models of colorectal and cervical cancer have demonstrated that LTβR activation induces tertiary lymphoid structures (TLSs), high endothelial venules (HEVs), and immune infiltration, thereby improving responsiveness to immune checkpoint blockade (ICB). This perspective examines in depth the functional duality of LTβR and its emerging therapeutic potential in solid tumors. LTβR agonism has been shown to promote TLS formation and immune activation, whereas antagonistic strategies such as ligand traps may suppress tumor-supportive LTβR signaling in immunosuppressive compartments. Strategically localized LTβR stimulation presents a promising avenue to induce targeted immune reprogramming within the TME. We further explore LTβR's interactions with key immune subsets-myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and tumor-associated macrophages (TAMs)-and its synergy with ICB and CAR T cell therapies. Selective LTβR modulation may reprogram the TME, overcome immunotherapy resistance, and broaden durable responses in refractory solid tumors.

Keywords:  anti-tumor immunity and immunotherapy; lymphotoxin beta receptor; lymphotoxin beta receptor pleiotropy; myeloid reprogramming; non-T cell-based immunotherapy; novel immunotherapeutic approaches; solid tumor immunity; solid tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1693507
Crit Rev Oncol Hematol. 2026 Feb 15. pii: S1040-8428(26)00106-X. [Epub ahead of print]221 105219

Antibody-nanoparticle conjugates for precision targeting of immunosuppressive tumor microenvironment.

Amir Saamaan Fattahi, Mahboobeh Jafari, Ghazal Farahavar, Elahe Haghighi, Samira Sadat Abolmaali, Ali Mohammad Tamaddon.

  Cancer continues to be a significant global health and socioeconomic issue, with an unequal mortality rate in low- and middle-income nations. The progression of tumors is influenced by both intrinsic changes within cancer cells and the tumor microenvironment (TME), which is a dynamic collection of stromal cells, immune infiltrates, extracellular matrix, and soluble mediators that together encourage immune suppression, angiogenesis, and resistance to treatment. Antibody-conjugated nanoparticles (ACNPs) combine antibody-mediated molecular recognition with nanoscale drug delivery systems to selectively target malignant cells and important components of the TME. In preclinical and early clinical studies, representative ACNP classes, including monoclonal antibodies or antibody fragments conjugated to liposomes, polymeric nanoparticles, metallic cores, or lipid-polymer hybrids, have exhibited enhanced tumor association and context-dependent intratumoral delivery, as well as the ability to modulate suppressive TME elements such as M2-like tumor-associated macrophages and cancer-associated fibroblasts. Nonetheless, clinical translation is impeded by significant biological and translational obstacles, such as tumor heterogeneity, restricted tissue penetration, swift elimination by the mononuclear phagocyte system, immunogenicity-associated safety concerns, and challenges in manufacturing and scaling up. In this paper, we critically examine ACNP design strategies, compare antibody formats and conjugation chemistries, and compile mechanistic evidence from in vitro, in vivo, and early clinical studies published up to 2025. We further investigate ACNP-based combination regimens targeting TME modulation and conclude by delineating translational priorities and practical design considerations necessary for achieving consistent therapeutic efficacy in heterogeneous human tumors.

Keywords:  Antibody-conjugated nanoparticles; Cancer immunotherapy; Drug delivery; Immunosuppressive; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105219
Front Immunol. 2026 ;17 1757513

Myeloid-derived suppressor cells and regulatory T cells in colorectal cancer: a synergistic immunosuppressive axis and emerging therapeutic opportunities.

Wenxing Zhang, Chenrui Jin, Shuyuan Liu, Xing Wan, Yu Li, Jifeng Liu, Zhijun Duan, Jingyuan Ma, Yunhai Gao.

  Microsatellite-stable (MSS)/proficient mismatch-repair (pMMR) colorectal cancer (CRC) accounts for more than 85% of cases but responds poorly to single-agent immune checkpoint inhibitors (ICIs), with objective response rates remaining below 5%. A principal barrier to effective immunotherapy in these tumors is a durable immunosuppressive axis formed by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) within the tumor microenvironment. This axis impedes antitumor immunity through multilayered mechanisms including bidirectional chemotactic recruitment, reciprocal cytokine signaling, metabolic suppression and exosome-mediated communication. CRC is uniquely influenced by the gut microbiota: Fusobacterium nucleatum promotes MDSC/Treg enrichment via TLR4-NF-κB and Fap2-TIGIT pathways; Peptostreptococcus anaerobius acts through integrin-PI3K-NF-κB signaling; and microbial metabolites such as 4-HPA activate JAK2/STAT3-CXCL3 signaling to expand MDSC populations. Concurrently, a hypoxia-lactate-HIF-1α-CD73/A2AR circuit further stabilizes suppressive phenotypes, forming a "microbiota-metabolism-hypoxia-MDSC-Treg" cascade. Emerging clinical and translational data indicate that disrupting this axis can sensitize MSS-CRC to ICIs: for example, Zanzalintinib combined with Atezolizumab reported survival benefit in the STELLAR-303 trial, and dual blockade of novel checkpoints with PD-(L)1 has been associated with enhanced immune activation in solid tumors. Targeting the MDSC-Treg axis therefore represents a promising strategy to overcome immunotherapy resistance in MSS/pMMR CRC.

Keywords:  MDSC; cold tumor; colorectal cancer; gut microbiota; immune checkpoint inhibitors; microsatellite stability; regulatory T cell

DOI:  https://doi.org/10.3389/fimmu.2026.1757513
Transl Res. 2026 Feb 13. pii: S1931-5244(26)00042-3. [Epub ahead of print]289 27-39

Targeting MAFB potentiates immune checkpoint inhibitor efficacy by reprogramming tumor-associated macrophages to an M1-like phenotype in colorectal cancer.

Sang-Pil Choi, Jun Yang, In-Byung Park, Seok-Jin Kang, Si-Won Park, Chang-Hee Lee, Hyeon Jeong Lee, Joonbeom Bae, Chang-Yong Choi, Jiyoon Shin, Ji-In Kim, Hyun Yong Jin, Young Sik Lee, Taehoon Chun.

  Colorectal cancer (CRC) remains largely resistant to immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumor microenvironment (TME) shaped by M2-like tumor-associated macrophages (TAMs). Identifying transcriptional regulators of M2-like TAMs in CRC could provide strategies to overcome ICI resistance by reprogramming the TME. In this study, we analyzed single-cell RNA-seq data from CRC patients to identify transcriptional regulators of M2-like TAMs. Notably, MAFB expression was predominantly detected in M2-like TAMs and was significantly higher in mismatch repair-proficient (pMMR) CRC than in mismatch repair-deficient (dMMR) CRC. Moreover, MAFB expression was inversely correlated with relapse-free survival in colon cancer patients. In macrophages, MAFB was induced by the IL-4-STAT6 and IL-10-STAT3 pathways, which drive M2 polarization, and was suppressed by M1-polarizing signals. Myeloid-specific deletion of Mafb, in combination with ICI treatment, reduced colon cancer growth by enhancing anti-tumor immunity through increased activity of M1-like TAMs, which led to increased infiltration of NK cells and activated cytotoxic T cells within the TME. Mechanistically, MAFB acts as a transcriptional activator directly promoting Il4ra, Il10, and Arg1 mRNA expression, supported by the identification of MAF recognition element (MARE) sites within these loci. Consistently, ectopic expression of IL-4 receptor α in Mafb-deficient macrophages restored M2 phenotypes comparable to those of wild-type macrophages. These data highlight the critical cell-intrinsic role of MAFB in regulating M2-like TAMs and provide the first evidence that targeting MAFB enhances ICI efficacy in CRC by reprogramming TAMs toward an anti-tumorigenic M1-like phenotype.

Keywords:  Colorectal cancer; Immune checkpoint inhibitor; MAFB; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.trsl.2026.02.006
Am J Clin Oncol. 2026 Feb 17.

Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.

Saikat Mandal, Arkadeep Dhali, Manideepa Maji, Guruprasad Aithal.

   OBJECTIVE: Biliary tract cancer (BTC) has a poor prognosis with limited therapeutic options. γδ T cells represent an MHC-independent immune cell population; however, their therapeutic efficacy in solid tumors is constrained by insufficient tumor infiltration. Chemokine-mediated trafficking is fundamental to T lymphocyte recruitment; however, the chemokine landscape of the BTC tumor microenvironment (TME) remains uncharacterized. Using single-cell RNA sequencing of BTC tissues, we delineated chemokine ligand expression patterns, stratified chemokine producers by lineage, assessed γδ T-cell recruitment mechanisms, and identified chemokine-mediated immune escape.
METHODS: We analyzed single-cell RNA sequencing data from 3 independent GEO cohorts (GSE210066, GSE201425, and GSE213452; 19 patients) to comprehensively delineate γδ T-cell mobilization-related chemokine expression across the BTC TME using the Seurat v5.0 pipeline in R.
RESULTS: Analysis identified a multiaxis chemokine profile within the BTC TME. High expression of CCL5, CCL4, and CCL3 established predominant CCR5-mediated recruitment axes supporting Vγ9Vδ2 T-cell infiltration, whereas CCL2 and modest CXCL8 supported CCR2+ and CXCR1+ Vδ1 T-cell recruitment. Notably, CXCL16 expression supported epithelial γδ T-cell homing through CXCR6. However, critical deficiencies in CXCL9 and CXCL10 suppress the IFN-γ-driven immunity. Paradoxically, chemokine axes supporting γδ T-cell recruitment (CCL2-CCR2, CXCL8-CXCR1, CXCL12-CXCR4) simultaneously recruit immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs).
CONCLUSION: Comprehensive single-cell analysis identified selective chemokine recruitment signatures supporting γδ T-cell infiltration but revealed paradoxical corecruitment of immunosuppressive populations. Patient stratification through chemokine profiling, combined with γδ T-cell enrichment and targeted chemokine antagonism, represents a rational therapeutic strategy.

Keywords:  adoptive cell therapy; biliary tract cancer; chemokines; cholangiocarcinoma; gallbladder cancer; γδ T-cell

DOI:  https://doi.org/10.1097/COC.0000000000001306
Med. 2026 Feb 16. pii: S2666-6340(26)00031-0. [Epub ahead of print] 101028

Current state of CAR-T cell therapies for solid tumors.

Reginaldo Rosa, Jiangyue Liu, Cathy Lu, Mohamed Abou-El-Enein, John P Murad, Saul J Priceman.

  Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies. However, its application in treating solid tumors has encountered significant obstacles. This review explores the current state of CAR-T cell therapy for solid tumors, highlighting challenges including the pronounced heterogeneity of tumor antigens and the immunosuppressive tumor microenvironment. We explore a range of preclinical and clinical strategies to enhance the efficacy of solid tumor CAR-T cells. These strategies encompass engineering chimeric receptors that can simultaneously target multiple antigens expressed by tumor cells, as well as implementing combination therapies and armored CAR-T cells to overcome existing limitations. While encouraging advancements using solid tumor CAR-T cell therapies have been seen, addressing intrinsic challenges remains a significant endeavor. Ongoing investigation of these innovative strategies is essential for the successful application of CAR-T cells in the context of solid tumors.

Keywords:  CAR-T cells; antigen heterogeneity; clinical trials; combination therapy; synthetic engineering; tumor microenvironment

DOI:  https://doi.org/10.1016/j.medj.2026.101028
Curr Osteoporos Rep. 2026 Feb 16. 24(1): 8

Metabolism in Tumour-Induced Bone Disease.

Renee T Ormsby, Claire M Edwards.

   PURPOSE OF REVIEW: This review highlights recent studies that investigate the metabolic reprogramming that occurs in specific types of bone metastatic cancers, including different types of breast cancer, prostate cancer and multiple myeloma.
RECENT FINDINGS: Metastatic cancer cells use altered metabolic pathways to adapt in alternate environments. Cancer cells that home towards the bone are able to manipulate their metabolism to survive in the hypoxic microenvironment, shifting between oxidative phosphorylation and glycolysis, whilst also exploiting neighbouring cells within the bone to provide energy and protect against chemotherapies. Targeting the altered metabolic pathways in cancer cells could be used to improve treatments, reduce tumour burden and prevent the destruction of the bone that occurs in tumour-induced bone disease.

Keywords:  Bone disease; Bone metastasis; Breast cancer; Cancer metabolism; Multiple myeloma; Prostate cancer

DOI:  https://doi.org/10.1007/s11914-026-00956-3
Clin Transl Med. 2026 Feb;16(2): e70628

The insider's perspective: The intracellular complosome and immune cell dynamics in cancer.

Alexandra Bennion, Joanne Lysaght, Niamh Lynam-Lennon.

  Complement is increasingly recognised as a driver and modulator of antitumour immunity, with context-dependent effects across T cells, myeloid subsets, stromal elements and tumour cells. Although best known for pathogen clearance and membrane attack complex (MAC) formation, complement also acts intracellularly via the 'complosome' to regulate cellular homeostasis and gene expression. Complosome activity may dampen antitumour responses by rewiring single-cell metabolism and transcription, altering nutrient flux and fostering an immunosuppressive microenvironment. Here, we synthesise advances in intracellular and extracellular complement, with emphasis on complement component 3 (C3) and receptors (C3aR1, C5aR1/CD88, C5aR2/C5L2), highlighting how these pathways shape T-cell metabolism, exhaustion programmes and inflammatory tone within tumours. Evidence indicates that tonic C3/C5 signalling restrains cytotoxicity via C5aR1-driven myeloid recruitment and cytokine cascades, while complosome signalling tunes T-cell activation thresholds and bioenergetics. We outline considerations for selectively modulating intracellular versus extracellular complement, propose cell-type-resolved biomarker strategies and identify opportunities for complosome-directed therapies in cancer, integrating roles across T cells, macrophages, B cells, neutrophils, NK cells, regulatory T cells, dendritic cells, myeloid-derived suppressor cells and cancer-associated fibroblasts. KEY POINTS: Intracellular complement (complosome) shapes the tumor immune microenvironment. Complosome's role in cancer is underrecognized yet central to tumor immunity. C3/C5-driven complosome signals rewire T cell activation, fate, and metabolism. Complosome activity can promote pro-tumor immune cell function. Blocking the complosome, alone or with checkpoint inhibitors, unveils a new tumor target.

Keywords:  C3; C3a; C5; C5a; cancer immunity; complement system; complosome; immune cells; immunotherapy; intracellular complement; tumour microenvironment

DOI:  https://doi.org/10.1002/ctm2.70628
Cell Death Differ. 2026 Feb 14.

Reprogramming the tumor microenvironment: methylmalonic acid at the intersection of ccRCC metabolism and macrophage polarization.

Jonatan Barrera-Chimal, Casimiro Gerarduzzi.

DOI: https://doi.org/10.1038/s41418-026-01685-x