bims-flamet 2026-03-15 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–03–15
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI

Drug Delivery Systems for Resiquimod to Control Myeloid-Derived Suppressor Cells in Cancer Immunotherapy.
Reprogramming innate immunity to overcome endocrine resistance in estrogen receptor-positive breast cancer.
Molecular mechanisms of tumor-associated macrophages in hepatocellular carcinoma development and therapy.
Immunosuppressive tumor microenvironment shape pancreatic cancer unresponsive to current immunotherapies.
The Conflicting Role of Myeloid Cells in CAR-T Cell Therapy.
MiRNAs: a call to arms that shapes the plasticity of tumor associated macrophages in breast cancer.
Dual Roles of MAIT Cells in the Tumor Microenvironment: Implications for Cancer Immunity and Therapy.
Metabolic networks in the tumor microenvironment: roles of amino acid and lipid metabolism pathways in cancer progression and therapy.
Multi-omics study on tumor-associated macrophages remodeling the tumor microenvironment via the CXCL5-CXCR2 axis to drive immune escape in bladder cancer.
[Heterogeneity of tumor-associated macrophages and precision targeting strategies in hepatocellular carcinoma].
Microenvironment plays a critical role in modulating tumor cell dormancy: Current perspectives and potential treatment options.
Complement system in cancer: friend or foe of immunotherapy.
Immunometabolism in lung cancer - The link between metabolism and immune response.
Immune Niches in Cancer.
Artificial intelligence-assisted spatial omics-based biomimetic nanoplatform for intelligent and precise intervention in the immunosuppressive core region of ovarian cancer.
Fatty Acid Metabolic Reprogramming in Gastrointestinal Tumor Microenvironment: Emerging Mechanisms and Therapeutic Opportunities.
Hypoxia-responsive self-assembled nanoparticles for reprogramming tumor-associated macrophages into an anti-tumor M1 phenotype in breast cancer.
IL33 in pancreatic cancer-pro- or antitumor?
Polarization of tumor-infiltrating macrophages predicts complete response to neoadjuvant treatment in patients with rectal cancer.
Targeting tumor-infiltrating regulatory T cells based on immunometabolism.
Dual Targeting of FAP-Directed Nanoparticles and FRα-Specific CAR-T Cells Induces Additive Anti-Tumor Effects in Triple-Negative Breast Cancer.

Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2026 Mar-Apr;18(2):18(2): e70052

Drug Delivery Systems for Resiquimod to Control Myeloid-Derived Suppressor Cells in Cancer Immunotherapy.

Yanying He, Yoon Yeo.

  Over the past decade, immunotherapy has emerged as the fourth pillar of cancer therapy, following surgery, chemotherapy, and radiotherapy. However, tumors often evade immune responses by altering the tumor microenvironment (TME), which recruits immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and regulatory T cells. Among these, MDSCs are considered key contributors to immunotherapy failure and have become major targets in new therapeutic strategies. Growing evidence indicates that controlling MDSCs is critical to the success of cancer immunotherapy, and several drug classes have shown feasibility. In this review, we introduce the significance of MDSCs as a target in cancer immunotherapy and highlight different therapeutic approaches to counteract their immunosuppressive functions. We discuss recent efforts to optimize drug delivery for controlling MDSCs, focusing on resiquimod (R848) as a representative drug candidate.

Keywords:  TLR7 agonist; cancer immunotherapy; drug delivery; immunosuppression; myeloid‐derived immunosuppressor cells; resiquimod

DOI:  https://doi.org/10.1002/wnan.70052
Int J Cancer. 2026 Mar 07.

Reprogramming innate immunity to overcome endocrine resistance in estrogen receptor-positive breast cancer.

Siti Nur Hasyila Muhammad, Maryam Azlan, Agustine Nengsih Fauzi.

  Estrogen receptor-positive (ER+) breast cancer accounts for the majority of breast cancer cases worldwide, yet the long-term efficacy of endocrine therapy is limited by resistance and recurrence. While tumor-intrinsic mechanisms of endocrine resistance are well established, growing evidence highlights the contributions of innate immune cells and the tumor microenvironment (TME) in shaping therapeutic outcomes. This review synthesizes recent advances into how tumor-associated macrophages (TAMs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs) collectively foster an immunosuppressive TME that undermines endocrine responsiveness. Central to this crosstalk is the STAT3 signaling pathway, which integrates inflammatory and metabolic stress signals to drive immune reprogramming, promotes tumor progression, and facilitates therapy resistance. By activating tolerogenic pathways and inhibiting anti-tumor immunity, STAT3 provides a mechanistic link between innate immune dysregulation and endocrine resistance. Preclinical studies demonstrate that STAT3 inhibition can restore tamoxifen sensitivity in resistant ER+ breast cancer models, highlighting its therapeutic potential. These insights reveal the immunological complexity of endocrine resistance and provide rationale for combinatorial strategies integrating endocrine therapy with immunomodulation. Future approaches that incorporate STAT3 inhibitor, immune checkpoint blockade, and biomarker-guided patient selection may transform the management of ER+ breast cancer, offering more durable and clinically meaningful outcomes by acknowledging the emerging interactions between immune dysregulation and metabolic stress in resistant ER+ breast cancer.

Keywords:  ER‐positive breast cancer; endocrine resistance; innate immunity; natural killer cells; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/ijc.70421
World J Gastroenterol. 2026 Feb 28. 32(8): 115675

Molecular mechanisms of tumor-associated macrophages in hepatocellular carcinoma development and therapy.

Ming Yang, Chun-Ye Zhang.

  Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks as the sixth most common cancer and the third leading cause of cancer-related death worldwide. Tumor-associated macrophages (TAMs) are predominant immune cells in the tumor microenvironment of HCC, playing critical roles in cancer cell proliferation, epithelial-mesenchymal transition, and metastasis. Reprogramming TAMs from a pro-tumoral phenotype to an anti-tumoral phenotype can enhance macrophage-mediated phagocytosis of HCC cells, improve cytotoxic T cell function, and increase the efficacy of immunotherapies. In this review, we summarize recent findings on how TAMs contribute to HCC development and progression, examine molecular markers and important signaling pathways that regulate TAM function within the tumor microenvironment, and discuss strategies for targeting TAMs at the cellular and molecular levels to treat HCC.

Keywords:  Hepatocellular carcinoma; Immune checkpoint inhibitors; Immunotherapy; Macrophages; Signaling pathways

DOI:  https://doi.org/10.3748/wjg.v32.i8.115675
World J Clin Oncol. 2026 Feb 24. 17(2): 114423

Immunosuppressive tumor microenvironment shape pancreatic cancer unresponsive to current immunotherapies.

Zong-Yang Li, Si-Yu Peng, Fei-Long Li, Hong-Qiao Cai.

  Pancreatic ductal adenocarcinoma remains largely refractory to current immunotherapies due to a profoundly immunosuppressive tumor microenvironment dominated by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). These cells form a coordinated network that suppresses cytotoxic T lymphocytes and fosters tumor progression. Key mechanisms include Tregs secreting inhibitory cytokines like transforming growth factor β and interleukin-10, and upregulating immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 and programmed death 1. MDSCs deplete essential nutrients like arginine and generate reactive oxygen species, while TAMs polarized to an M2 phenotype produce chemokines including C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 12, which recruit more suppressive cells. Single-cell transcriptomic studies have uncovered prognostically relevant cellular subsets, such as caspase-4-high Tregs, highlighting this heterogeneity. Reciprocal signaling via interleukin-10 and transforming growth factor β creates a self-reinforcing immunosuppressive loop. Emerging therapeutic strategies aim to disrupt this axis by depleting Tregs (e.g., anti-CD25), blocking MDSC recruitment (e.g., CCR2 inhibitors), or reprogramming TAMs (e.g., CD40 agonists), often in combination with programmed death 1/programmed death-ligand 1 blockade. An integrated approach targeting these populations holds promise for converting pancreatic ductal adenocarcinoma into an immunologically responsive tumor.

Keywords:  Immunosuppressive tumor microenvironment; Myeloid-derived suppressor cells; Pancreatic ductal adenocarcinoma; Regulatory T cells; Tumor-associated macrophages

DOI:  https://doi.org/10.5306/wjco.v17.i2.114423
Cancer Res. 2026 Mar 12.

The Conflicting Role of Myeloid Cells in CAR-T Cell Therapy.

Grace DeFranco, Elizabeth L Siegler, Saad S Kenderian.

Chimeric antigen receptor T (CAR-T) cell therapy is revolutionizing cancer treatment in hematological malignancies, but challenges related to the tumor microenvironment have hindered CAR-T success, especially in solid tumors. Myeloid cells in particular have been implicated in CAR-T efficacy. In this review, we discuss the roles of myeloid cells in CAR-T-associated toxicities including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, along with strategies to treat these toxicities by modulating myeloid cells. The review also explores myeloid cell-mediated suppression or enhancement of CAR-T function. Finally, strategies employed to target myeloid cells in combination with CAR-T cell therapy will be investigated.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4817
Front Immunol. 2026 ;17 1792965

MiRNAs: a call to arms that shapes the plasticity of tumor associated macrophages in breast cancer.

Valentina Fogazzi, Giulia Cosentino, Michele Sommariva, Angela Galardi, Elisa Dell'Orto, Serenella M Pupa, Cristian Taccioli, Marilena V Iorio.

  Breast cancer (BC) remains a leading cause of cancer-related mortality, and a major contribution to tumor progression and resistance to therapies arise from tumor microenvironment (TME). Tumor is indeed able to shape a self-permissive TME, reprogramming the cellular components into allies. Tumor-associated macrophages (TAMs), abundant in BC TME, mainly acquire an immunosuppressive M2-like phenotype able to fuel tumor progression, immune evasion, metastasis and therapy resistance through a dynamic crosstalk with cancer cells. MicroRNAs, transferred via extracellular vesicles and exploited by the tumor to mold an immunesuppressive niche, act as central mediators of this bidirectional communication: tumor-derived miRNAs can reprogram macrophages toward an M2-like functional program, and TAM-derived miRNAs in turn promote and sustain cancer cell progression. This miRNA-orchestrated plasticity highlights TAMs as key TME regulators. Clinically, miRNA modulation offers promising strategies for TAM reprogramming, alongside their utility as prognostic biomarkers. Integrating miRNA-targeted TME interventions with conventional therapies holds the potential to overcome resistance in high-TAM BC subtypes.

Keywords:  breast cancer; immune evasion; microRNAs; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1792965
Immune Netw. 2026 Feb;26(1): e8

Dual Roles of MAIT Cells in the Tumor Microenvironment: Implications for Cancer Immunity and Therapy.

Junghwan Choi, You Jeong Lee.

  Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize riboflavin metabolites with canonical TCRs and develop in the thymus as memory cells. They account for 1%-10% of peripheral blood T cells in humans and are frequently observed within the tumor microenvironment (TME). However, their functional roles remain controversial. In certain tumors, infiltrated MAIT cells upregulate cytotoxic receptor NKG2D and effector cytokines, including IFNγ, TNFα, and granzyme, contributing to tumor control. In other settings, they exhibit reduced cytokine production, increased expression of inhibitory receptors such as PD-1, CTLA-4, and TIM-3, and are associated with unfavorable clinical outcomes. These discrepancies are influenced by the source of MR1 ligands, cytokine composition, and metabolic conditions within the TME. Meanwhile, due to the innate cytotoxicity and lack of alloreactivity, MAIT cells are attractive candidates for cellular immunotherapy. This review summarizes the functional dichotomy of MAIT cells in cancers and outlines strategies to harness their anti-tumor properties.

Keywords:  Immunotherapy; Mucosal-associated invariant T cells; Tumor

DOI:  https://doi.org/10.4110/in.2026.26.e8
Exp Mol Med. 2026 Mar 13.

Metabolic networks in the tumor microenvironment: roles of amino acid and lipid metabolism pathways in cancer progression and therapy.

Yulseung Sung, Dae Kyoung Kim, Jun Se Kim, Seong-Jang Kim, Jae Ho Kim, Jung Min Han.

Metabolic rewiring, a defining hallmark of cancer, sustains cell proliferation and biosynthesis while coordinating adaptive interactions within the tumor microenvironment (TME). Recent advances reveal that metabolism in the TME-comprising stromal, immune and endothelial components forms a complex metabolic network in which intercellular competition, cooperation and plasticity profoundly influence tumor progression and therapeutic responses. Here we integrate emerging evidence on the organizational principles of amino acid and lipid metabolism within the TME, emphasizing how nutrient fluxes shape immune evasion, therapeutic resistance and metabolic symbiosis. We highlight key mechanisms through which cancer and nonmalignant cells engage in reciprocal nutrient manipulation, focusing on glutamine, arginine, tryptophan, branched-chain amino acids and lipids. The dual roles of these metabolites in immune regulation and tumor growth reveal the limitations of traditional single-pathway targeting and advocate for a network-centric therapeutic approach. We further discuss how metabolite-derived signaling and epigenetic regulation reinforce cell state transitions and immune suppression. Current and emerging therapeutic strategies, including multitarget combinations and immune-metabolic synergies, are evaluated alongside translational challenges. Finally, we underscore the need for spatial metabolomics, liquid biopsy platforms and artificial intelligence-driven modeling to map nutrient competition and cooperative exchange within the TME, offering new opportunities for precision metabolic interventions.

DOI: https://doi.org/10.1038/s12276-026-01697-0
Cancer Immunol Immunother. 2026 Mar 11. pii: 103. [Epub ahead of print]75(4):

Multi-omics study on tumor-associated macrophages remodeling the tumor microenvironment via the CXCL5-CXCR2 axis to drive immune escape in bladder cancer.

Yunzhong Jiang, Jianpeng Li, Zezhong Yang, Minghai Ma, Lu Wang, Lu Zhang, Minxuan Jing, Yaodong Zhang, Yuanchun Pu, Yutong Chen, Jiale He, Hang Liu, Xiaowei Qu, Mengzhao Zhang, Jinhai Fan.

   BACKGROUND: PD-1/L1 inhibitors improve the prognosis of patients with advanced bladder cancer, but the clinical remission rate remains below 25%. Tumor-associated macrophages (TAMs) and chemokines are critical in the tumor microenvironment (TME), affecting tumor progression, immunotherapeutic efficacy, and patient prognosis; however, their underlying mechanisms remain unclear. This study exhibits innovation by adopting a tumor microenvironment perspective to investigate the interaction mechanism between bladder cancer cells and tumor-associated macrophages, as well as factors affecting the efficacy of immunotherapy.
METHODS: Single-cell sequencing, bulk sequencing, and in vivo experiments identified TAM infiltration characteristics, their impacts on prognosis and immunotherapy. In vitro, we established a co-culture model and performed targeted metabolomic sequencing on TAMs. Xenograft and tail vein metastasis models were used to investigate the function of CXCL5-CXCR2 axis in bladder TME.
RESULTS: M2 macrophages were positively correlated with the clinical staging of bladder cancer and resistance to immunotherapy. Single-cell sequencing data revealed that CXCL5+ tumor-associated macrophages (TAMs) were associated with poor overall survival but a favorable response to immunotherapy, whereas FOLR2+ TAMs were linked to both poor overall survival and immunotherapy resistance. The CXCL5-CXCR2-NF-κB axis was upregulated in the co-culture system, which promoted PD-L1 expression in both tumor cells and TAMs, the formation of an immunosuppressive tumor microenvironment (TME), as well as the migration, proliferation, and lung metastatic potential of bladder cancer cells. Additionally, this axis enhanced IDO1 expression in macrophages and improved the efficacy of immunotherapy for bladder cancer.
CONCLUSION: The CXCL5-CXCR2 axis mediates bladder cancer cell-macrophage crosstalk: macrophages promote tumor growth, immune escape, and cisplatin tolerance; tumor cells induce macrophage polarization and reshape immunosuppressive TME. Additionally, this axis drives bladder cancer malignant progression and enhances immunotherapy efficacy.

Keywords:  CXCL5–CXCR2; Immune escape; PD-L1; Tumor-associated macrophage

DOI:  https://doi.org/10.1007/s00262-026-04353-8
Zhonghua Gan Zang Bing Za Zhi. 2026 Feb 20. 34(2): 174-179

[Heterogeneity of tumor-associated macrophages and precision targeting strategies in hepatocellular carcinoma].

K Huang, G Q Zhang.

Tumor-associated macrophages (TAMs) are abundant immune cell content in the tumor microenvironment of hepatocellular carcinoma and are associated with tumor progression and therapeutic resistance. This article describes novel TAM subpopulations and potential targets in hepatocellular carcinoma that have been identified based on single-cell and spatial omics technologies. Additionally, it proposes TAMs' classification according to their functions into immunosuppressive, lipid-metabolizing, angiogenic, liver-resident, and immune-stimulating types and summarizes four major therapeutic strategies targeting TAMs, providing a reference for novel TAM-targeted therapies.

DOI: https://doi.org/10.3760/cma.j.cn501113-20250714-00276
World J Clin Oncol. 2026 Feb 24. 17(2): 114298

Microenvironment plays a critical role in modulating tumor cell dormancy: Current perspectives and potential treatment options.

Ye-Rong Qian, Peng Liu, Hui Xu, Yi Lv, Xu-Feng Zhang, Jun-Xi Xiang.

  Tumor dormancy is a fundamental phenomenon in cancer biology, characterized by malignant cells that remain viable but non-proliferative, thereby frequently evading detection and treatment. This review examines the intricate role of the tumor microenvironment (TME) in regulating tumor cell dormancy. The TME encompasses a diverse array of components, including immune cells, extracellular matrix proteins, and soluble factors, all of which contribute to a dynamic interplay that influences tumor cell behavior. Key mechanisms involved in the maintenance of dormancy include immune surveillance, where immune cells can either suppress or promote tumor growth, and extracellular matrix interactions that provide structural support and biochemical signals essential for quiescence. Additionally, microenvironmental conditions such as hypoxia and acidosis impose selective pressures that can favor dormant states over active proliferation. Emerging therapeutic strategies are being explored to target dormant tumor cells, including the use of mesenchymal stem cell therapies, which may modulate the TME to either awaken dormant cells for targeted treatment or maintain their quiescent state to prevent recurrence. Understanding the TME's influence on tumor dormancy not only enhances our comprehension of cancer progression but also opens avenues for innovative treatments aimed at improving patient outcomes by mitigating the risks of recurrence and metastasis. This article aims to provide a comprehensive overview of the current knowledge on TME-mediated tumor dormancy and highlight promising therapeutic strategies for future research.

Keywords:  Cancer recurrence; Extracellular matrix; Metastasis; Tumor dormancy; Tumor microenvironment

DOI:  https://doi.org/10.5306/wjco.v17.i2.114298
J Immunother Cancer. 2026 Mar 11. pii: e013290. [Epub ahead of print]14(3):

Complement system in cancer: friend or foe of immunotherapy.

Harendra Kumar Shah, Sai Prem, Xiaobo Wu, M Kathryn Liszewski, John P Atkinson, Abhay Kumar Singh, Vaishali Kapoor.

  The complement system, a key component of the immune response, plays a dual role in cancer, influencing both tumor suppression and progression. Its three activation pathways (classical, alternative, and lectin) initiate immune processes, including opsonization and cell lysis. Within the tumor microenvironment, however, complement activation can paradoxically support immune-mediated tumor control or contribute to immune evasion and tumor growth. Therapeutic interventions such as radiation and certain chemotherapies can trigger complement activation by inducing immunogenic cell death and the release of damage-associated molecular patterns. This activation leads to the generation of anaphylatoxins C3a and C5a, which recruit immune cells to the tumor site and promote antitumor immunity. However, these same fragments may also foster an immunosuppressive microenvironment by attracting regulatory T cells and myeloid-derived suppressor cells, thereby limiting the efficacy of immunotherapies. Additionally, tumor cells often upregulate membrane complement regulatory proteins, including CD46, CD55, and CD59, to escape complement-mediated cytotoxicity and immune surveillance. Recent insights indicate that the complement system is a critical barrier to effective immunotherapy. Complement inhibition, particularly by targeting C3a receptor and C5a receptor 1, has been shown to synergize with immune checkpoint inhibitors (eg, anti-programmed cell death protein-1/programmed death-ligand 1), reversing complement-driven immunosuppression and enhancing T cell-mediated tumor rejection. Combining complement blockade with proimmunogenic therapies such as radiation or chemotherapy may further amplify these effects by uncoupling therapy-induced complement activation from its immunosuppressive consequences. Thus, the interplay between complement activation and cancer therapeutics presents a promising avenue for treatment innovations. Strategic modulation of complement, whether through genetic, pharmacologic, or antibody-based approaches, could sensitize tumors to immunotherapy and help overcome resistance mechanisms. Continued investigation into this crosstalk will be essential for designing effective combination strategies that maximize antitumor immunity while minimizing immune escape.

Keywords:  Complement; Immune modulatory; Immunotherapy; Radiotherapy/radioimmunotherapy; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-013290
iScience. 2026 Mar 20. 29(3): 115041

Immunometabolism in lung cancer - The link between metabolism and immune response.

Yasamin Eivazzadeh, Niloufar Orooji, Tamana Eskandari, Mahdieh Tarahomi, Fatemeh Tavassoli Razavi, Dariush Haghmorad.

  Lung cancer remains a leading cause of cancer-related mortality worldwide, characterized by complex interactions between tumor metabolism and immune evasion mechanisms. This review explores the emerging field of immunometabolism, highlighting how metabolic reprogramming within lung tumors not only fuels cancer progression but also shapes the tumor immune microenvironment (TME). Key metabolic pathways, such as glycolysis, glutaminolysis, and lipid metabolism, are extensively altered in lung cancer cells, facilitating immune suppression through mechanisms such as nutrient competition, lactate accumulation, and modulation of immune checkpoints. Immune cells, including tumor-associated macrophages (TAMs), T cells, NK cells, and dendritic cells, undergo functional impairment due to these metabolic constraints. The review further discusses therapeutic strategies targeting immunometabolic pathways, including inhibitors of glucose and amino acid transporters, lipid biosynthesis enzymes, and immune-metabolic checkpoints such as IDO and CD73. Despite promising preclinical outcomes, challenges such as metabolic plasticity, systemic toxicity, and limited biomarker availability hinder clinical translation. Future directions emphasize the integration of multi-omics, metabolic profiling, and combinatory immunotherapy to personalize treatment and overcome resistance. A deeper understanding of immunometabolic crosstalk is pivotal for advancing precision medicine in lung cancer.

Keywords:  Cancer; Immunology

DOI:  https://doi.org/10.1016/j.isci.2026.115041
Annu Rev Immunol. 2026 Mar 13.

Immune Niches in Cancer.

Nadine Slingerland, Eline Runderkamp, Daniela S Thommen.

Emerging evidence underscores a key role for the tumor microenvironment in supporting or suppressing cancer immunity. Of note, pro- and antitumor immune activity is controlled by not only the types of immune cells present but also their spatial arrangement within a tumor. This evidence is supported by the observation that the organization of immune cells in specialized immune niches is more predictive for clinical outcome and immunotherapy response than is the mere presence of tumor immune infiltrates. In this review, we explore how spatial compartmentalization modulates immune function through concerted cellular interactions, localized signaling cascades, and the generation of protective environments. We integrate current knowledge on both established and emerging immune niches with variable complexity-shaped by cell diversity, cell density, and structural organization-and their functional impact on cancer immunity. Finally, we discuss the compelling therapeutic opportunities offered by the induction or modulation of these niches in tumors.

DOI: https://doi.org/10.1146/annurev-immunol-082724-123843
NPJ Precis Oncol. 2026 Mar 11.

Artificial intelligence-assisted spatial omics-based biomimetic nanoplatform for intelligent and precise intervention in the immunosuppressive core region of ovarian cancer.

JinKe Li, Weilin Liu, Yu Mu, Xiaoxue Wang, Hefeng Zhang, Kexin Tang, Dandan Zhang.

Ovarian cancer (OC) ranks among the most aggressive malignancies of the female reproductive system. The immunosuppressive tumor microenvironment (TME) and pronounced spatial heterogeneity significantly restrict the efficacy of immunotherapy. Recent advances in single-cell omics and spatial transcriptomics (ST) have enabled the identification of immunosuppressive core regions within the TME at molecular and spatial levels. These regions often contain "exclusion structures" composed of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) in hypoxia-enriched niches. To achieve precise therapeutic modulation of these core microregions, researchers have developed biomimetic nanodrug platforms such as cell membrane-coated systems and exosome-based carriers. These platforms deliver immunoregulatory agents targeting programmed death-ligand 1 (PD-L1), transforming growth factor-beta (TGF-β), and colony-stimulating factor 1 receptor (CSF1R), with enhanced efficiency and adaptability through multi-responsive mechanisms. The paper provides a comprehensive review of the spatial organization mechanisms, omics-based identification methods, and signaling network pathways that define the immunosuppressive core regions in OC. It also summarizes the design principles and adaptive strategies of biomimetic platforms and introduces an artificial intelligence (AI)-assisted closed-loop therapeutic framework encompassing identification, delivery, and feedback to support individualized and precise immunotherapy. Although the approach demonstrates strong potential for multidimensional integration, several challenges remain, including the standardization of spatial atlases, the stability of delivery systems, and cross-platform compatibility, all of which require further technological advancement.

DOI: https://doi.org/10.1038/s41698-026-01345-w
Crit Rev Oncol Hematol. 2026 Mar 07. pii: S1040-8428(26)00146-0. [Epub ahead of print] 105259

Fatty Acid Metabolic Reprogramming in Gastrointestinal Tumor Microenvironment: Emerging Mechanisms and Therapeutic Opportunities.

Xiangdi Sun, Yuhan Shen, Xingyan Lv, Jiaxin Tian, Xiaoshuo Dai, Jing Lu.

  Gastrointestinal (GI) tumors, characterized by high incidence and mortality rates, represent a major global health challenge. Metabolic reprogramming has been recognized as one of their defining hallmarks. Beyond aberrant glucose metabolism, accumulating evidence has revealed how dysregulated fatty acid (FA) metabolism plays a multifaceted role in regulating the tumor microenvironment (TME). By modulating tumor, immune, and stromal cells, FA metabolism profoundly influences tumorigenesis, progression, and cell death. Despite advances in current treatments, the inherent immunosuppressive nature of TME and the therapeutic resistance of tumor cells still remain major obstacles. Notably, targeting key nodes of FA metabolism has emerged as a promising strategy to overcome these challenges. Thus, in this review, we systematically delineate how FA metabolic reprogramming shapes the GI tumor microenvironment by regulating tumor, immune, and stromal cells in multiple ways. Furthermore, we critically explore the translational potential of FA metabolism in biomarker development, targeted therapy, and combination therapeutic strategies. By synthesizing these insights, this review aims to provide forward-looking perspectives on future therapeutic strategies against GI tumors.

Keywords:  Combined therapeutic strategies; Fatty acid; Gastrointestinal tumor; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105259
Mater Today Bio. 2026 Apr;37 102956

Hypoxia-responsive self-assembled nanoparticles for reprogramming tumor-associated macrophages into an anti-tumor M1 phenotype in breast cancer.

Xiaoyan Fu, Huayong Zhang, Weimin Liu, Tingting Wu, Yizi Zheng.

  The tumor microenvironment is characterized by hypoxia, resulting mainly from aberrant vascularization and insufficient blood perfusion. Under such hypoxic conditions, tumor-associated macrophages (TAMs) preferentially polarize toward an immunosuppressive M2-like phenotype, which promotes immune evasion and accelerates tumor progression. Reprogramming these M2-like TAMs into an anti-tumor M1 phenotype represents a promising therapeutic strategy, yet it remains a substantial challenge. In this study, we developed nanoparticles functionalized with mannose and an MMP-2-responsive PLGVRGD peptide. These nanoparticles undergo self-assembly in the presence of matrix metalloproteinase-2 (MMP-2), which is highly expressed in hypoxic tumor regions. The high-density mannose residues on the nanoparticle surface facilitate efficient binding to M2-like TAMs and promote their repolarization to the M1 phenotype. Moreover, the resulting system exhibits enhanced tumor tissue penetration and effectively reverses the immunosuppressive tumor microenvironment, supporting its potential as a targeted nanotherapeutic strategy for breast cancer.

Keywords:  MMP-2; Macrophage repolarization; Self-assembled nanoparticles; Tumor hypoxia

DOI:  https://doi.org/10.1016/j.mtbio.2026.102956
Trends Cancer. 2026 Mar 10. pii: S2405-8033(26)00022-1. [Epub ahead of print]

IL33 in pancreatic cancer-pro- or antitumor?

Supriya Sharma, Ajay Dixit.

  Interleukin 33 (IL33) in the tumor microenvironment of pancreatic cancer has been linked to both pro- and antitumor immune responses, suggesting a context-dependent role. Herein, we discuss the current understanding and challenges of therapeutically targeting IL33 signaling in pancreatic cancer.

Keywords:  IL33; ST2; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.01.009
Oncoimmunology. 2026 Dec 31. 15(1): 2641261

Polarization of tumor-infiltrating macrophages predicts complete response to neoadjuvant treatment in patients with rectal cancer.

Aylin Alkan, Fabian Byvald, Rode Grönkvist, Gustaf Danielsson, Joshua Cumming, Peter Falk, Eva Angenete, Ulf Yrlid.

  Characterizing the composition of immune cells in the tumor microenvironment (TME) has shown promise in understanding variable responses to neoadjuvant treatment in rectal cancer. Despite this, no method has been established that can confidently predict the response to pre-operative chemoradiotherapy. Tumor-associated macrophages (TAMs) in the TME can be polarized by the biochemical milieu to adopt pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes. Utilizing the spectrum of TAM polarization as a biomarker to predict patient response to neoadjuvant therapy in rectal cancer patients has not been fully explored. We address this using 7-plex immunofluorescence staining to quantify 16 subsets of TAMs in rectal adenocarcinoma pretreatment biopsies. Pretreatment biopsies were obtained from 128 patients with known tumor regression grades (TRG). Through quantifying the prevalence of TAM subsets, we identified a higher density of the completely M1-polarized subset and a lower density of the completely M2-polarized subset in patients with a complete pathological response, the absence of detectable tumor cells following treatment. Predictive modeling using TAM subsets showed that only the densities of two completely polarized subsets were predictors of therapeutic response in patients with rectal cancer. Significantly, we demonstrate that the full panel of markers we employed were required to define predictive populations, as total TAMs or TAM subsets defined by fewer markers were incapable of predicting treatment response. Taken together, we validate the utility of a multiplex approach to define the spectrum of TAM polarization, which can be leveraged to identify patients that will have a complete pathological response to neoadjuvant treatment.

Keywords:  Macrophage polarization; neoadjuvant treatment; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1080/2162402X.2026.2641261
Cancer Biol Med. 2026 Mar 10. pii: j.issn.2095-3941.2025.0645. [Epub ahead of print]23(2):

Targeting tumor-infiltrating regulatory T cells based on immunometabolism.

Na Li, Dexue Tian.

  The immune checkpoint blockade (ICB) approach in cancer therapy involves the disruption of immune checkpoint inhibitory signals on tumor-specific CD8+ T cells, thereby reinstating the immune activity of CD8+ T cells and yielding therapeutic efficacy. However, due to the co-expression of immune checkpoint molecules, such as CTLA-4 and PD-1 on tumor-infiltrating Tregs (TI-Tregs) and conventional T cells (Tconvs), immune checkpoint inhibitors (ICIs) inadvertently amplify the immunosuppressive activity of Tregs while targeting CD8+ T cells, which contributes to the failure of immune therapy. Conventional strategies targeting Tregs, including ICI/conventional kinase and chemokine/chemokine receptor blockade, generally induce systemic Treg depletion, which triggers autoimmune diseases. Thus, achieving high selectivity and specificity in targeting TI-Tregs is of paramount importance in mitigating adverse immunologic reactions. Targeting metabolism-based TI-Tregs has been shown to enhance target precision, providing potential for the development of adjunctive immunotherapeutic strategies. This article explores the reciprocal interaction between TI-Tregs and the tumor microenvironment (TME), elucidating metabolic reprogramming, while envisioning plausible high-selectivity targets for TI-Tregs without compromising systemic immune homeostasis and immune reactivity of effector T cells.

Keywords:  CD8+ T cells; Tumor-infiltrating regulatory T cells; immune checkpoint inhibitors; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0645
Int J Biol Sci. 2026 ;22(5): 2736-2753

Dual Targeting of FAP-Directed Nanoparticles and FRα-Specific CAR-T Cells Induces Additive Anti-Tumor Effects in Triple-Negative Breast Cancer.

Tanva Thongkleang, Suyanee Thongchot, Kamonlatth Rodponthukwaji, Piriya Luangwattananun, Kwanruthai Tadpetch, Pa-Thai Yenchitsomanus, Peti Thuwajit, Primana Punnakitikashem, Chanitra Thuwajit.

  Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. It lacks hormone receptors and human epidermal growth factor receptor 2. The immunosuppressive tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), significantly hinders chimeric antigen receptor (CAR)-T cell therapy success. Novel strategies to overcome TME-mediated immunosuppression are urgently needed. We evaluated whether targeting CAFs with fibroblast activation protein alpha (FAP)-coated, 8-O-methylfusarubin-loaded nanoparticles called anti-FAP@OMF-NPs could enhance the anti-tumor efficacy of folate receptor alpha (FRα)-specific CAR-T cells against TNBC in a 3D cancer cells-CAFs co-culture heterospheriod (HS) model. FRα and FAP expression in TNBC cells and primary breast CAFs were assessed using immunofluorescence and flow cytometry. Anti-FRα-CAR-T cells were generated via lentiviral transduction and characterised for activation markers. Cytotoxic activity of CAR-T cells, anti-FAP@OMF-NPs, and their combination was evaluated in 3D-HS comprising FRα-high TNBC cells and FAP-high CAFs. A fluorescent transfection assay measured cell viability. Cytokine bead arrays quantified IFN-γ, granzyme A, and granzyme B levels to assess anti-tumor immune activation. PC-B-130CAFs and PC-B-132CAFs demonstrated high FAP expression compared with PC-B-004CAFs and normal human dermal fibroblast cells (HDFa). Anti-FRα-CAR-T cells selectively targeted FRα-positive TNBC cells whilst showing minimal cytotoxicity towards normal MCF-10A cells. Anti-FAP@OMF-NPs induced potent cytotoxic effects specifically in FAP-expressing CAFs. Combined treatment significantly enhanced the destruction of MDA-MB-231/130CAF and MDA-MB-231/132CAF HSs compared with monotherapies. This combination increased secretion of IFN-γ, granzyme A, and granzyme B from anti-FRα-CAR-T cells. Targeting CAFs using anti-FAP@OMF-NPs enhances the cytotoxic efficacy of FRα-specific CAR-T cells in TNBC. This combinatorial approach offers a promising strategy to overcome TME-mediated immunosuppression. These findings support further development of dual-targeting approaches to improve therapeutic outcomes in TNBC.

Keywords:  Cancer-associated fibroblast; Chimeric antigen receptor-T cell; Fibroblast activation protein alpha; Folate receptor alpha; Nanoparticle; Triple-negative breast cancer

DOI:  https://doi.org/10.7150/ijbs.122417