bims-flamet 2025-05-25 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–05–25
29 papers selected by
Peio Azcoaga, Biodonostia HRI

Novel metabolic routes to cancer immune evasion.
Paclitaxel, interferons and functional reprogramming of tumor-associated macrophages in optimized chemo-immunotherapy.
The Rab25-ADAMTS5 axis as a previously undescribed mechanism for sensing tumor microenvironment complexity.
Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy.
YTHDF2: a key RNA reader and antitumor target.
Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment.
Oxidative complexity: The role of ROS in the tumor environment and therapeutic implications.
Elucidating the tumor microenvironment interactions in breast, cervical, and ovarian cancer through single-cell RNA sequencing.
Metabolic Profiling of Tumor and Immune Cells Integrating Seahorse and Flow Cytometry.
Phospholipid Scramblases TMEM16F and Xkr8 regulate distinct features of Phosphatidylserine (PS) externalization and immune regulation in the tumor microenvironment to regulate tumor growth.
Immunotherapy in Microsatellite-Stable Colorectal Cancer: Strategies to Overcome Resistance.
The relevance of B7-H3 and tumor-associated macrophages in the tumor immune microenvironment of solid tumors: recent advances.
Harnessing Exosomes: From Tumor Immune Escape to Therapeutic Innovation in Gastric Cancer Immunotherapy.
Exosomes in bridging macrophage-fibroblast polarity and cancer stemness.
Reprogramming tumor-associated macrophages using STING or TLR agonists: a promising strategy to enhance immunotherapy in hormone-dependent cancers.
Biofilm formation by the host microbiota: a protective shield against immunity and its implication in cancer.
EMT induction in normal breast epithelial cells by COX2-expressing fibroblasts.
Tumor microenvironment and immune-related myositis: addressing muscle wasting in cancer immunotherapy.
Immune exclusion in hepatoblastoma: is β-catenin to blame again?
Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.
Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.
The predictive value of peripheral blood monocytic myeloid-derived suppressor cells for survival and immunotherapy responses in tumor patients.
A novel pH-sensitive nanoparticles encapsulating anti-PD-1 antibody and MDK-siRNA overcome immune checkpoint blockade resistance in HCC via reshaping immunosuppressive TME.
Decoding the function of Cancer-Associated Fibroblasts in Osteosarcoma: Molecular pathways, therapeutic approaches and prognostic significance.
Bisecting GlcNAc expression by bone marrow stromal cells modulates TGF-β1-driven macrophage polarization in myeloid leukemias.
Matrix stiffness-driven cancer progression and the targeted therapeutic strategy.
Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity via the cGAS/STING pathway.
Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.
Adjusting the scope of natural killer cells in cancer therapy.

Trends Cancer. 2025 May 19. pii: S2405-8033(25)00125-6. [Epub ahead of print]

Novel metabolic routes to cancer immune evasion.

Ayoub Jaa, Aitziber Buque.

  The tumor microenvironment (TME) comprises heterogeneous cell types that closely interact with each other. Crosstalk among the TME components determines antitumor immune responses and their sensitivity to therapies such as immunotherapy. Recent studies published in Cancer Cell by Tang et al. and Zhu et al. identify two novel metabolic adaptations that tumors use to facilitate immune evasion. These targetable mechanisms suggest new avenues to improve antitumor immune responses.

Keywords:  amino acids; arginine; breast cancer; immunology; metabolism; tryptophan; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2025.05.002
J Immunother Cancer. 2025 May 19. pii: e010960. [Epub ahead of print]13(5):

Paclitaxel, interferons and functional reprogramming of tumor-associated macrophages in optimized chemo-immunotherapy.

Pawel Kalinski, Kathleen M Kokolus, Shipra Gandhi.

  Immune checkpoint inhibition (ICI) targeting programmed cell death protein-1 (PD1) prevents the elimination of activated cytotoxic T lymphocytes (CTLs) by programmed death-ligand 1/2-expressing cancer and myeloid cells in the tumor microenvironment (TME). ICI has shown its effectiveness in many solid tumors, but it lacks activity against "cold" tumors which lack CTL infiltration, including most of the colon, prostate, lung and breast cancers. Metastatic triple-negative breast cancer (TNBC) responds to PD-1 blockade only in 5-20% cases. Chemotherapy has been shown to have a PD1-sensitizing effect in a fraction of patients with TNBC but the underlying mechanism and the reasoning behind its limitation to only a subset of patients are unknown. Recent data demonstrate the key roles played by paclitaxel-driven Toll-like receptor 4 (TLR4) signaling and the resulting activation of type-1 and type-2 interferon pathways in tumor-associated macrophages, resulting in local M2 to M1 transition and enhanced tumor antigen cross-presentation, in the paclitaxel-driven sensitization of "cold" tumors to ICI. These data and the known ability of the TLR4-activated MyD88-NFκB pathway to mobilize both antitumor and tumor-promoting events in the TME provide new tools to enhance the efficacy of chemo-immunotherapy for metastatic, and potentially early, TNBC and other taxane-sensitive cancers.

Keywords:  Chemotherapy; Immune Checkpoint Inhibitor; Macrophage

DOI:  https://doi.org/10.1136/jitc-2024-010960
FEBS J. 2025 May 23.

The Rab25-ADAMTS5 axis as a previously undescribed mechanism for sensing tumor microenvironment complexity.

François Tyckaert, Francesco Baschieri.

  The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a critical role in cancer progression. Focusing on ovarian cancer, Yuan et al. reveal an ECM-dependent signaling axis where cancer-associated fibroblasts (CAFs) enhance the invasiveness of cancer cells via Rab25-driven upregulation of the protease ADAMTS5. This process is only triggered in the presence of native ECM. In turn, stimulated cancer cells favor CAF invasiveness through a mechanism that remains to be identified. These findings uncover a bidirectional crosstalk between cancer cells and CAFs and highlight the importance of context-specific in vitro models to decipher ECM-mediated tumor dynamics.

Keywords:  CAF; cancer; extracellular matrix; metastasis

DOI:  https://doi.org/10.1111/febs.70147
J Exp Clin Cancer Res. 2025 May 16. 44(1): 145

Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy.

Yan Yang, Sijia Li, Kenneth K W To, Shuangli Zhu, Fang Wang, Liwu Fu.

  Despite the significant advances in the development of immune checkpoint inhibitors (ICI), primary and acquired ICI resistance remains the primary impediment to effective cancer immunotherapy. Residing in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a pivotal role in tumor progression by regulating diverse signaling pathways. Notably, accumulating evidence has confirmed that TAMs interplay with various cellular components within the TME directly or indirectly to maintain the dynamic balance of the M1/M2 ratio and shape an immunosuppressive TME, consequently conferring immune evasion and immunotherapy tolerance. Detailed investigation of the communication network around TAMs could provide potential molecular targets and optimize ICI therapies. In this review, we systematically summarize the latest advances in understanding the origin and functional plasticity of TAMs, with a focus on the key signaling pathways driving macrophage polarization and the diverse stimuli that regulate this dynamic process. Moreover, we elaborate on the intricate interplay between TAMs and other cellular constituents within the TME, that is driving tumor initiation, progression and immune evasion, exploring novel targets for cancer immunotherapy. We further discuss current challenges and future research directions, emphasizing the need to decode TAM-TME interactions and translate preclinical findings into clinical breakthroughs. In conclusion, while TAM-targeted therapies hold significant promise for enhancing immunotherapy outcomes, addressing key challenges-such as TAM heterogeneity, context-dependent plasticity, and therapeutic resistance-remains critical to achieving optimal clinical efficacy.

Keywords:  Immune checkpoint inhibitors; Immune evasion; Immunotherapy; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s13046-025-03377-9
Trends Immunol. 2025 May 20. pii: S1471-4906(25)00095-X. [Epub ahead of print]

YTHDF2: a key RNA reader and antitumor target.

Sai Xiao, Songqi Duan, Michael A Caligiuri, Shoubao Ma, Jianhua Yu.

  N6-methyladenosine (m6A) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major m6A 'reader', was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8+ T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.

Keywords:  RNA metabolism; YTHDF2; immunotherapy; m(5)C; m(6)A; tumor immunology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.it.2025.04.003
J Immunother Cancer. 2025 May 15. pii: e011292. [Epub ahead of print]13(5):

Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment.

Jenna H Rannikko, Rita Turpin, Pia Boström, Reetta Virtakoivu, Chantal Harth, Akira Takeda, Anselm Tamminen, Ilkka Koskivuo, Maija Hollmén.

   BACKGROUND: Tumor-associated macrophages (TAMs) adapt to the tumor microenvironment (TME), either aiding cancer eradication or promoting tumor growth and immune evasion. To manipulate TAMs therapeutically, a deep understanding of their interaction with the TME is essential. This study explores the responsiveness of TMEs to bexmarilimab, a macrophage reprogramming therapy showing clinical benefit in various solid tumors.
METHODS: We exploited a breast cancer patient-derived explant culture (PDEC) model to characterize bexmarilimab responses in both tumor and adjacent cancer-free tissues by RNA sequencing and multiplex cytokine profiling. Using single-cell RNA sequencing, spatial transcriptomics, and conditioned media treatment, we further investigated the effects of Clever-1+ macrophages and TME features on bexmarilimab sensitivity.
RESULTS: The PDEC model captured key aspects of bexmarilimab's mode of action and validated a gene signature for determining treatment sensitivity. We identified three distinct responses to bexmarilimab in tumors and adjacent cancer-free tissues, shaped by the local microenvironment and macrophage phenotype, origin, and localization. The inflammatory state of the TME emerged as the primary determinant of response. Immune activation occurred in immunologically cold TMEs lacking late-stage activated TAMs, whereas interferon-regulated TMEs exhibited suppressed inflammation. In cancer-free breast tissue, bexmarilimab activated B cell responses independent of treatment sensitivity in the adjacent tumor.
CONCLUSIONS: These findings reveal the complexity of TAM targeting in cancer and emphasize the need for patient selection to maximize bexmarilimab's efficacy.

Keywords:  Breast Cancer; Immunotherapy; Macrophage; Monoclonal antibody

DOI:  https://doi.org/10.1136/jitc-2024-011292
Bioorg Med Chem. 2025 May 15. pii: S0968-0896(25)00182-8. [Epub ahead of print]127 118241

Oxidative complexity: The role of ROS in the tumor environment and therapeutic implications.

Tingfeng Shen, Yutong Wang, Linmao Cheng, Ann M Bode, Ya Gao, Shuntong Zhang, Xue Chen, Xiangjian Luo.

  Reactive oxygen species (ROS) constitutes a group of reactive molecules that play a critical role in biological processes. Varying ROS levels have been frequently observed in cancer cells and the tumor microenvironment (TME). The role of ROS displays significant complexity in cancer development and therapy. Elevated ROS levels can induce metabolic reprogramming and promote the proliferation, invasion, and metastasis of cancer cells, resulting in cancer progression. However, excessive ROS accumulation leads to the occurrence of apoptosis, pyroptosis, necroptosis, and ferroptosis in cancer cells, which restrains tumor development. In the TME, ROS frequently promotes angiogenesis and remodels the extracellular matrix (ECM) by enhancing the differentiation of cancer-associated fibroblasts (CAFs), thereby supporting tumor growth. Concurrently, high ROS levels favour immunosuppressive cells, including M2-polarized macrophages, and regulatory T cells (Tregs), while impairing the antitumor capabilities of T cells. In the aspect of cancer therapy, it is overly simplistic to merely combine chemoradiotherapy with antioxidants as a therapeutic strategy. Instead, highlighting targeted therapies that modulate ROS is essential, given their inherent complexity. Fortunately, a variety of innovative treatments have emerged, including nanodrug delivery systems (NDDS), proteolysis-targeting chimeras (PROTAC), and adoptive cell therapy (ADT), which not only exhibit synergistic effects with immune checkpoint therapy (ICT), but also enhance the antitumor capabilities of the TME. In this paper, we elucidate the mechanism of ROS production, enumerate the role of ROS in cancer development and the TME, and discuss advancements in ROS-targeted cancer therapeutics.

Keywords:  Cancer; Cell death; Immunotherapy; Metabolic reprogramming; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bmc.2025.118241
Sci Rep. 2025 May 22. 15(1): 17846

Elucidating the tumor microenvironment interactions in breast, cervical, and ovarian cancer through single-cell RNA sequencing.

Xiaoyue Zhu, Liang Zhang, Xiaomin Yu, Pengxian Yan, Xiaoyu Zhang, Yunlong Zhao, Dongze Wang, Xiu-An Yang.

  This study aimed to identify the key cell types and their interactions in gynecological oncology of breast cancer, cervical cancer, and ovarian cancer. Single-cell RNA sequencing was performed on tumor samples of gynecological oncology from the GEO database. Cell types were identified using SingleR and cell composition was analyzed to understand the tumor microenvironment (TME). CellChat was used to analyze cell interactions, and pseudotemporal analysis was conducted on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) to understand their differentiation status. Four CAF subtypes were identified: iCAF, myCAF, proCAF, and matCAF. The iCAF subpopulation secreted COL1A1 and promoted tumor cell migration, while myCAF was involved in angiogenesis. The matCAF subpopulation was present throughout tumor development. TAMs were found to promote angiogenesis through the VEGFA_VEGFR2 signaling pathway. CAFs and TAMs play pivotal roles in tumor progression through their interactions and signaling pathways.

Keywords:  Angiogenesis; Cancer-associated fibroblasts; Single-cell RNA sequencing; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1038/s41598-025-03017-4
Methods Mol Biol. 2025 ;2930 103-126

Metabolic Profiling of Tumor and Immune Cells Integrating Seahorse and Flow Cytometry.

Nienke B Goedhart, Helga Simon-Molas.

  Studying metabolism in the different cellular compartments of the tumor microenvironment (TME) is crucial to identify the specific metabolic signatures that contribute to tumor progression. Additionally, TME-driven metabolic changes can disrupt the essential metabolic processes involved in immune cell function, hindering immunotherapy success. Extracellular flux analysis (Seahorse) is a well-established approach used to characterize cellular metabolism. When combined with flow cytometry-based measurements, it offers a comprehensive view of the metabolic signatures within the different cellular compartments of the TME. Here we provide a detailed description on the procedures of Seahorse analysis and complementary flow cytometry-based metabolic readouts on tumor cells and T cells in the context of cancer, which can also be applied to other physiological and pathological situations.

Keywords:  Extracellular flux analysis; Flow cytometry; Immunotherapy; Metabolism; Mitochondria; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-4558-1_9
bioRxiv. 2025 Apr 18. pii: 2025.04.17.649445. [Epub ahead of print]

Phospholipid Scramblases TMEM16F and Xkr8 regulate distinct features of Phosphatidylserine (PS) externalization and immune regulation in the tumor microenvironment to regulate tumor growth.

Varsha Gadiyar, Rachael Pulica, Ahmed Aquib, James A Tranos, Christopher Varsanyi, Luis Fernandez Almansa, Lawrence Gaspers, Mariana De Lorenzo, Sergei V Kotenko, Sushil Tripathi, Roger W Howell, Alok Choudhary, David C Calianese, Raymond B Birge.

The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) on cells by distinct molecular mechanisms. Xkr8, a caspase-activated scramblase, is activated by caspase-mediated proteolytic cleavage, and in synergy with caspase-mediated inactivation of P4-type ATP-dependent flippases, results in the irreversible externalization of PS on the dying cells and an "eat-me" signal for efferocytosis. In contrast, TMEM16F is a calcium activated scramblase that reversibly externalizes PS on viable cells via the transient increase in intracellular calcium on activated or growth factor stimulated cells. By contrast to the abovementioned homeostatic mechanisms of PS externalization under physiological conditions, PS becomes constitutively externalized in the tumor microenvironment (TME) in many solid tumor types by a complex mechanistic, posited both via the high apoptotic indexes of tumors, but also by the prolonged oncogenic and metabolic stresses that occur in the TME. Such chronic and persistent PS externalization in the TME has been linked to host immune evasion and the tonic interactions of PS with inhibitory PS receptors such as TAM (Tyro3, Axl, Mertk) and TIM (T cell/transmembrane, immunoglobulin, and mucin) family receptors. Here, in an effort to better understand the contributions of apoptotic vs live cell PS-externalization with respect to tumorigenesis and immune evasion, we employed an E0771 luminal B breast cancer orthotopic in vivo model and genetically ablated Xkr8 and TMEM16F using CRISPR/Cas9. While neither the knockout of Xkr8 nor TMEM16F showed defects in cell intrinsic properties related to cell growth, tumor sphere formation, cell migration, and growth factor signaling, both knockouts suppressed tumorigenicity in immune-competent mice, but not in NOD/SCID or RAG deficient immune-deficient strains. Mechanistically, at the cell biological level, Xkr8 knockout suppressed macrophage-mediated efferocytosis, and TMEM16F knockout suppressed ER stress/calcium-induced PS externalization. Our data support an emerging idea in immune-oncology and immunotherapy that constitutive PS externalization, mediated by the activation of scramblases on tumor cells, can support immune evasion in the tumor microenvironment thereby linking a combination of apoptosis/efferocytosis and oncogenic stress involving calcium dysregulation the contribute to PS-mediated immune escape and cancer progression.

DOI: https://doi.org/10.1101/2025.04.17.649445
Crit Rev Oncol Hematol. 2025 May 21. pii: S1040-8428(25)00163-5. [Epub ahead of print] 104775

Immunotherapy in Microsatellite-Stable Colorectal Cancer: Strategies to Overcome Resistance.

Engeng Chen, Wei Zhou.

  Colorectal cancer (CRC) is among the foremost causes of cancer-related mortality worldwide; however, individuals with microsatellite-stable (MSS) disease-who constitute most CRC diagnoses-derive limited benefit from existing immunotherapeutic approaches. Here, we outline emerging methods designed to address the inherent resistance of MSS CRC to immune checkpoint inhibitors (ICIs). Recent findings emphasize how the immunosuppressive tumor microenvironment (TME) in MSS CRC, marked by diminished immunogenicity and high levels of regulatory T cells and myeloid-derived suppressor cells, restricts effective antitumor immune activity. Combination regimens that merge ICIs with chemotherapy, anti-angiogenic agents, or targeted blockade of pathways such as TGF-β and VEGF have shown encouraging early outcomes, including enhanced antigen presentation and T-cell penetration. Novel immunomodulatory platforms-such as epigenetic modifiers, oncolytic viruses, and engineered probiotic vaccines-are under assessment to further reprogram the TME and boost therapeutic efficacy. Concurrently, progress in adoptive cell therapies (for example, chimeric antigen receptor (CAR) T cells) and the development of cancer vaccines targeting tumor-associated and neoantigens promise to extend immune control over MSS CRC. In parallel, improving patient selection through predictive biomarkers-from circulating tumor DNA (ctDNA) to gene expression signatures and specific molecular subtypes-could refine individualized treatment strategies. Finally, interventions that alter the gut microbiome, including probiotics and fecal transplantation, serve as complementary tools to strengthen ICI responses. Taken together, these insights and combined treatment strategies lay the foundation for more successful immunotherapeutic interventions in MSS CRC, ultimately aiming to provide sustained clinical benefits to a broader spectrum of patients.

Keywords:  Combination Therapy Strategies; Immunotherapy Resistance Mechanisms; Microsatellite-Stable Colorectal Cancer; Neoadjuvant Immunotherapy; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104775
Am J Transl Res. 2025 ;17(4): 2835-2849

The relevance of B7-H3 and tumor-associated macrophages in the tumor immune microenvironment of solid tumors: recent advances.

Shuo Luan, Yuwei Zhao, Yiyang Yu, Jie Xu, Jiuhui Xu, Tingting Ren, Xiaodong Tang, Lu Xie.

  B7 homolog 3 (B7-H3) is a member of the B7 ligand family. It is highly expressed in various human cancers, especially mesenchymal malignancies. B7-H3 regulates cancer progression through multiple signaling pathways such as JAK2/STAT3, NF-κB, PI3K/AKT, and ERK. It also has the ability to downregulate CD8+ T-cell infiltration and drive immune evasion. Tumor-associated macrophages (TAMs) are the primary immune infiltrating cells in diverse solid tumors, dominating the immune environment of these malignancies. B7-H3 may have connections to TAMs through the induction of polarization and immunosuppression by the CCL2-CCR2-M2 macrophage axis. This mechanism can inhibit antitumor immunotherapy and promote tumor progression in non-small cell lung cancer, ovarian cancer, colorectal cancer, and osteosarcoma. The inducibility of B7-H3 in TAMs provides novel insight into the targeting of checkpoints for tumor immunotherapy. In general, B7-H3 represents a promising immune therapeutic target and should be considered an immunologic adjuvant for activating the tumor immune microenvironment. Therefore, combination therapies based on anti-B7-H3 agents hold great potential for improving the solid tumor microenvironment to enhance the initiation of the cancer-immunity cycle.

Keywords:  B7-H3; immunotherapy; macrophages; tumor microenvironment

DOI:  https://doi.org/10.62347/ILTR3848
Cancer Lett. 2025 May 21. pii: S0304-3835(25)00359-3. [Epub ahead of print] 217792

Harnessing Exosomes: From Tumor Immune Escape to Therapeutic Innovation in Gastric Cancer Immunotherapy.

Zhao Jin, Cheng Zhang, Lin Shen, Yanshuo Cao.

  Gastric cancer ranks fifth among the most prevalent cancers globally, with a dismal prognosis. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a glimmer of hope for advanced gastric cancer patients. However, not all patients can benefit from this treatment modality, as the tumor microenvironment significantly influences treatment efficacy. Exosomes, pivotal mediators of intercellular communication, exert intricate and diverse effects in shaping and regulating the tumor microenvironment. This review provides a comprehensive overview of the functional mechanisms of exosomes within the gastric cancer tumor microenvironment. It delves into their biogenesis, functions, and impact on innate and adaptive immune cells (such as dendritic cells, myeloid-derived suppressor cells, and T cells) and cancer-associated fibroblasts. Additionally, the potential applications of exosomes in gastric cancer immunotherapy are explored, including their use as biomarkers to predict responses to immune checkpoint inhibitors, and drug delivery vectors, and in the development of exosome-based vaccines and gene therapy. Notably, this review emphasizes the dual nature of exosomes: they can facilitate tumor immune escape, yet they also serve as promising targets for innovative therapeutic strategies. It also compares potential exosome-based strategies with existing immunotherapies like ICIs and emerging CAR-T cell therapies. Finally, insights into the future of exosomes in precision immunotherapy for gastric cancer are offered, presenting a forward-looking perspective on this emerging field.

Keywords:  Exosomes; Gastric Cancer; Immunotherapy; Therapy; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217792
Med Oncol. 2025 May 21. 42(6): 216

Exosomes in bridging macrophage-fibroblast polarity and cancer stemness.

Keywan Mortezaee.

  Exosome roles in cellular cross-talking within tumor microenvironment (TME) is a critical event in tumorigenesis. Type 2 macrophages (M2), cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs) are the three most important cells in cancer progression and metastasis, and targeting their connectome route can be an effective anti-cancer strategy. Exosomes mediate bidirectional cross-talking between the three cell types in which exosomes secreted from CSCs promote polarization of M2 macrophages and CAFs, and that M2- and CAF-derived exosomes promote cancer stemness through activation of epithelial-mesenchymal transition (EMT)-related signaling including transforming growth factor (TGF)-β, WNT/β-catenin and epidermal growth factor (EGF). CSC-derived exosomal TGF-β is a key driver of CAF and M2 macrophage polarization, with the latter mediated through activation of signal transducer and activator of transcription 3 (STAT3). β-catenin activity also seems to take important role in exosomal cross-talk between CAFs and stemness state of cancer. Incubation of exosomes with inhibitors of signaling inter-connecting CSCs, M2 and CAFs is a key anti-cancer strategy and a promising supplementary to the routine immunotherapeutic approaches in cancer therapy.

Keywords:  Cancer stem cell (CSC); Cancer-associated fibroblast (CAF); Epithelial-mesenchymal transition (EMT); Exosome; Transforming growth factor (TGF); Type 2 macrophage (M2)

DOI:  https://doi.org/10.1007/s12032-025-02774-6
J Immunother Cancer. 2025 May 15. pii: e010950. [Epub ahead of print]13(5):

Reprogramming tumor-associated macrophages using STING or TLR agonists: a promising strategy to enhance immunotherapy in hormone-dependent cancers.

Victor Sacristan Santos, Alba Pensado-López, Rosario García-Campelo, Silvia Antolin Novoa, Rosa Señaris Rodriguez, Fernando Torres Andón.

  Hormone-dependent cancers, like breast and prostate cancers, represent a unique challenge in oncology due to their complex interplay between hormone signaling, immune evasion, and therapeutic resistance. While endocrine therapies effectively target hormone signaling to initially control disease, resistance mechanisms frequently emerge, leading to cancer progression and limited survival. These solid tumors further complicate treatment by establishing an immunosuppressive tumor microenvironment (TME), presenting variable numbers of immune cells depending on cancer type and stage, which hinders the efficacy of immune checkpoint inhibitors. In this TME, tumor-associated macrophages (TAMs) are the major cellular source of immunosuppression, supporting tumor growth. The ability of TAMs to hamper the effectiveness of endocrine therapy is becoming increasingly recognized. Reprogramming TAMs within solid tumors can restore their natural ability to fight cancer and also enhance antitumoral efficacy. In this line of research, Al-Janabi et al have recently developed lipid nanoparticles decorated with antibodies that bind to the folate receptor-beta overexpressed in perivascular TAMs and loaded with a STING agonist (cGAMP) for the reprogramming of these TAMs. In preclinical murine models of prostate cancer, this therapeutic approach demonstrated significant synergistic activity with androgen deprivation therapy. This work provides an excellent example of TAM reprogramming combined with endocrine therapy for the treatment of hormone-dependent cancers.

Keywords:  Immunotherapy; Macrophage; Nanoparticle; Solid tumor; Toll-like receptor - TLR

DOI:  https://doi.org/10.1136/jitc-2024-010950
Mol Cancer. 2025 May 21. 24(1): 148

Biofilm formation by the host microbiota: a protective shield against immunity and its implication in cancer.

Elena Montanari, Giancarla Bernardo, Valentino Le Noci, Martina Anselmi, Serenella M Pupa, Elda Tagliabue, Michele Sommariva, Lucia Sfondrini.

  Human-resident microbes typically cluster into biofilms - structurally organized communities embedded within a matrix of self-produced extracellular polymeric substance (EPS) that serves as a protective shield. These biofilms enhance microbial survival and functional adaptability, favoring a symbiotic relationship with the host under physiological conditions. However, biofilms exhibit a dual role in modulating the immune response. If their ability to promote tolerance is key to safeguarding homeostasis, by contrast, their persistence can overcome the cutting-edge balance resulting in immune evasion, chronic inflammation and development of numerous diseases such as cancer. Recent evidence highlights the significance of cancer-associated microbiota in shaping the tumor microenvironment (TME). These microbial inhabitants often exhibit biofilm-like structures, which may protect them from host immune responses and therapeutic interventions. The presence of biofilm-forming microbiota within the TME may promote chronic inflammation, and release of bioactive molecules that interfere with immune surveillance mechanisms, thereby enabling cancer cells to evade immune destruction. This review delves into the complex interplay between biofilms and cancer, with particular focus on the tumor-associated microbiota and the implications of biofilm involvement in modulating the immune landscape of the TME. Addressing this intricate relationship holds promises for innovative therapeutic approaches aimed at reprogramming the microbiota-cancer axis for better clinical outcomes.

Keywords:  Biofilm; Cancer; Immune modulation; Microbiota

DOI:  https://doi.org/10.1186/s12943-025-02348-0
Cell Commun Signal. 2025 May 22. 23(1): 237

EMT induction in normal breast epithelial cells by COX2-expressing fibroblasts.

Minwoo Kang, Somayadineshraj Devarasou, Nam Ji Sung, Tae Yoon Kwon, Jennifer H Shin.

   BACKGROUND: The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevated COX2 expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect of COX2-expressing CAFs (COX2+ CAFs) on neighboring cells and their consequent role in cancer progression is not fully elucidated.
METHODS: We induced COX2+ fibroblasts by forcing the fibroblasts forming aggregates to undergo Nemosis as a proxy for COX2+ CAFs. This approach enabled us to simulate the paracrine interactions between COX2+ CAFs and normal breast epithelial cells via conditioned media from COX2+ fibroblasts. We developed an innovative in vitro platform that combines cell mechanics-based analysis and biomolecular assays to study the interactions between COX2+ fibroblasts and normal breast epithelial cells. By focusing on the mechanical characteristics of the cells and the epithelial-mesenchymal transition (EMT) marker expressions, we aimed to elucidate the paracrine mechanisms through which COX2+ CAFs influence the tumor microenvironment.
RESULTS: Our in vitro findings demonstrate that COX2+ fibroblasts, through conditioned media, induce significant alterations in the mechanical behavior of normal breast epithelial cells, as evidenced by monolayer expansion measurements using traction force microscopy (TFM). This transition was further corroborated by single-cell morphology and motility analyses, as well as increased expression of mesenchymal markers, including SNAI1 at the mRNA level and vimentin at the protein level. EP4 inhibition partially reversed these changes, preserving cell-cell interactions, limiting monolayer expansion, and reducing mesenchymal-like features, suggesting that PGE2-EP4 signaling plays a key role in mediating the paracrine effects of COX2+ fibroblasts. Together, our findings support a model in which PGE2-EP4 signaling contributes to EMT induction, potentially involving SNAI1 regulation, with implications for targeting stromal-epithelial interactions in breast cancer.
CONCLUSION: This study advances our understanding of the potential mechanisms by which COX2+ CAFs influence tumor progression within the breast tumor microenvironment (TME) through controlled in vitro investigations. By integrating cell mechanics-based analysis, biomolecular assays, and innovative in vitro cell-based modeling of COX2+ CAFs, we have delineated the contributory role of these cells in a controlled setting. These insights lay a groundwork for future studies that could explore the implications of these findings in vivo, potentially guiding targeted therapeutic strategies.

Keywords:   COX2 ; Breast cancer; Cancer-associated fibroblasts; EMT; Fibroblasts; Nemosis; PGE2; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-025-02227-7
Front Immunol. 2025 ;16 1580108

Tumor microenvironment and immune-related myositis: addressing muscle wasting in cancer immunotherapy.

Shuang Ma, Guangyu Zhao, Shang Sui, Xiankai Chen, Linxin Wu, Taihang Wang, Wanying Xu, Zhijiao Lu, Andong Wang, Xiaolin Wu, Jiaxuan Wu, Yi Liu, Tao Yan.

  Cancer immunotherapy, which leverages the immune system to target neoplastic cells, has undergone significant transformation in recent. However, immunotherapy may have negative effects on skeletal muscle function, causing muscle wasting and functional decline in cancer patients. In this study, we review the mechanisms by which immunotherapy influences skeletal muscle, focusing on immune-related myositis, inflammation, and metabolic alterations within the tumor microenvironment (TME). The key methodologies, including biomechanical assessment techniques such as electrical impedance myography and ultrasound imaging, are discussed to provide valuable insights into process that maintain muscle integrity and function in patients receiving immunotherapy. Moreover, the dual effects of immunotherapy on tumor suppression and muscle damage are described, revealing the significance of inflammatory cytokines, immune checkpoints, and metabolic disturbances within the TME. Importantly, we propose combination therapies integrating immunotherapy and nutritional interventions or anti-inflammatory interventions as potential approaches for mitigating muscle wasting. This study highlights the need for deeper investigations to optimize immunotherapy and improve its efficacy in preserving muscle health, thereby improving patient outcomes and quality of life.

Keywords:  cancer immunotherapy; inflammatory cytokines; muscle wasting; skeletal muscle; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1580108
J Hepatol. 2025 May 21. pii: S0168-8278(25)02203-2. [Epub ahead of print]

Immune exclusion in hepatoblastoma: is β-catenin to blame again?

Theo Z Hirsch.



Keywords:  CTNNB1; Wnt pathway; hepatoblastoma; immune evasion; liver cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.jhep.2025.05.005
Sci Adv. 2025 May 23. 11(21): eadv0558

Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.

Xiaozhen Zhang, Mengyi Lao, Kang Sun, Hanshen Yang, Lihong He, Xinyuan Liu, Linyue Liu, Sirui Zhang, Chengxiang Guo, Sicheng Wang, Jiatao Shi, Xiaoyu Zhang, Daqian Xu, Xiongbin Lu, Xueli Bai, Tingbo Liang.

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.

DOI: https://doi.org/10.1126/sciadv.adv0558
Cell Signal. 2025 May 15. pii: S0898-6568(25)00289-X. [Epub ahead of print]133 111874

Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.

Tingyu Chen, Yiming Xu, Fan Yang, Yanxin Pan, Ning Ji, Jing Li, Xin Zeng, Qianming Chen, Lu Jiang, Ying-Qiang Shen.

  Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.

Keywords:  Cancer cells; Cancer-associated fibroblasts; Glutamine; Metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2025.111874
BMC Immunol. 2025 May 24. 26(1): 41

The predictive value of peripheral blood monocytic myeloid-derived suppressor cells for survival and immunotherapy responses in tumor patients.

Wanying Sheng, Yan Ding, Yuting Su, Jing Hu, Lu Wang, Minjie Guo, Xiao Yuan, Deqiang Wang, Chunhua Dai, Xu Wang.

   BACKGROUND AND OBJECTIVES: The identification of affordable and easily accessible indicators to predict overall survival is important for tumor immunotherapy. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which promote tumor immune escape in the tumor microenvironment (TME). This study aimed to determine whether peripheral blood MDSCs could determine their potential as predictors of survival in tumor patients with immunotherapy.
METHODS: Flow cytometry was used to detect peripheral blood monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic myeloid-derived suppressor cells (G-MDSCs) in 126 patients. Multivariate Cox regression analysis was conducted to examine the associations between peripheral blood MDSCs and patient survival. The receiver operating characteristic (ROC) curve determined the optimal cutoff value for peripheral blood MDSCs and grouped the indicators. The relationship between peripheral blood M-MDSCs and the prognosis and treatment outcome of tumor patients was explored.
RESULTS: The proportion of peripheral blood M-MDSCs was associated with the prognosis of patients with tumors, as were tumor metastasis, the red blood cell count, absolute neutrophil count, absolute monocyte count, and BMI. Multivariate Cox regression analysis revealed that M-MDSCs, absolute lymphocyte value, and tumor metastasis were independent risk factors affecting the prognosis of patients with tumors. Detection of peripheral blood M-MDSCs obtained high sensitivity and specificity for tumor diagnosis. Patients with high M-MDSCs percentage demonstrated reduced survival durations and diminished responses to immunotherapy compared to those with low M-MDSCs percentage.
CONCLUSIONS: Peripheral blood M-MDSCs may be used to predict overall survival and immunotherapy efficacy outcomes. This study provides a putative predictive biomarker for clinicians to choose from to predict tumor patients' survival and the selection of receiving immunotherapy regimens.

Keywords:  Immunotherapy response; MDSCs; Overall survival; Peripheral blood; Predictive value

DOI:  https://doi.org/10.1186/s12865-025-00722-7
J Exp Clin Cancer Res. 2025 May 16. 44(1): 148

A novel pH-sensitive nanoparticles encapsulating anti-PD-1 antibody and MDK-siRNA overcome immune checkpoint blockade resistance in HCC via reshaping immunosuppressive TME.

Hai Xu, Shuo Li, Yifan Liu, Yoon-Young Sung, Yong Zhou, Huikun Wu.

   OBJECTIVE: Immunotherapy, notably the immune checkpoint blockade (ICB), has demonstrated significant promise in the management of diverse neoplasms. However, the PD-1 inhibitor has exhibited suboptimal objective response rates and did not achieve the primary endpoints in hepatocellular carcinoma (HCC) patients, primarily due to resistance to ICB fostered by the immunosuppressive tumor microenvironment (TME). To address ICI resistance and minimize adverse effects, we have engineered an innovative tumor-specific nanomedicine for the concurrent administration of aPD-1 and MDK-siRNA.
METHODS: Both in vitro and orthotopic HCC models were employed to investigate and establish the efficacy of the novel tumor-specific nanomedicine in overcoming the immunosuppressive TME. Specifically, the impact of the nanomedicine on the M2 polarization and polyamine metabolism within tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was delineated. The immunomodulatory and antitumor effects, along with the side effects, of the nanomedicine integrating both aPD-1 and MDK-siRNA were assessed.
RESULTS: A dual pH-responsive nanomedicine was successfully fabricated to co-deliver MDK-siRNA and aPD-1. The nanomedicine achieved targeted drug delivery to tumors by engaging with circulating PD-1+ T cells and accompanying their migration into the tumor mass. Additionally, nanomedicine promoted efficient drug release within the acidic TME, deploying aPD-1 for ICI therapy and retaining MDK-siRNA-encapsulated nanomedicine to regulate TAMs and MDSCs synergistically. The synergistic application of MDK-siRNA and aPD-1, coupled with the efficient tumor-targeted drug delivery, potently suppressed M2 polarization and polyamine metabolism in TAMs and MDSCs, thereby overcoming the immunosuppressive TME and leading to significant therapeutic efficacy with minimal side effects in HCC.
CONCLUSION: We have developed an innovative tumor-specific nanocarrier for the co-delivery of aPD-1 and MDK-siRNA. We validated that the synthesized nanomedicine (aPD-1-siRNA@NP) yielded highly effective treatment and minimal side effects in both in vitro and orthotopic HCC models. Our work presents a nanomedicine-based approach for targeted dual-drug delivery, achieving notable efficacy in the treatment of HCC.

Keywords:  Hepatocellular carcinoma; Immunotherapy; Midkine; Myeloid-derived suppressor cells; Nanodrug; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s13046-025-03396-6
Exp Cell Res. 2025 May 20. pii: S0014-4827(25)00208-3. [Epub ahead of print] 114612

Decoding the function of Cancer-Associated Fibroblasts in Osteosarcoma: Molecular pathways, therapeutic approaches and prognostic significance.

Chou-Yi Hsu, Ali G Alkhathami, Thanaa Amir Ahmed, Muktesh Chandra, Jaafaru Sani Mohammed, H Malathi, Krishan Kumar Sah, Ashish Singh Chauhan, Ahmad Iwadi, Abbas Fadhel Ali.

  Herein, we summarize the latest insights into osteosarcoma, the most prevalent primary malignant bone tumor, known for its aggressive nature, poor outcome, and especially poor prognosis when metastasis develops. Given recent research implicating the crucial role of the tumor microenvironment (TME) in osteosarcoma progression, cancer-associated fibroblasts (CAFs) emerged as key players. Through the secretion of cytokines, remodeling of the extracellular matrix (ECM), and cross-talk with osteosarcoma cells, CAFs collectively promote tumor growth, metastasis, and immune evasion. Exosomes derived from CAFs, which could also serve as important mediators of osteosarcoma progression, have been found to transport oncogenic lncRNAs like SNHG17 and linc00881. Moreover, some subtypes of CAFs, such as TOP2A+ CAFs, have shown significant prognostic value for tumor aggressiveness. Thus, targeted CAFs was identified as a promising therapeutic modality, with strategies such as fibroblast activation protein (FAP) inhibition, TGF-β blockade, and CXCL12/CXCR4 axis inhibition demonstrating positive outcomes in preclinical models. The combination of CAF-targeted therapies with immunotherapies or chemotherapy has shown additional potential to reverse this CAF-induced resistance. Autophagy regulation in CAFs can be therapeutic opportunities for novel Interevent strategies.

Keywords:  Cancer-associated fibroblasts; Molecular Mechanisms; Osteosarcoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.yexcr.2025.114612
Haematologica. 2025 May 22.

Bisecting GlcNAc expression by bone marrow stromal cells modulates TGF-β1-driven macrophage polarization in myeloid leukemias.

Jingjing Feng, Junjie Gou, Yi Wang, Wei Wei, Yihan Ma, Xueting Ren, Chongfu Zhao, Xiaoliang Cheng, Lei Lei, Zengqi Tan, Feng Guan, Xiang Li.

Accumulating evidence have highlighted the critical role of tumor-associated macrophages (TAMs) in promoting immune evasion and disease progression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in bone marrow of MDS/AML reveal a shift toward a tumor-supportive M2-polarized macrophage as well as the expression of programmed cell death-ligand 1 (PD-L1) in this cell lineage. We found the leukemic stroma cells with high level of TGFβ1 secretion can determine TAMs toward M2-polarized subtype. Further mechanistic investigations revealed that bone marrow stromal cells with specific glycans, reduced bisecting N-acetylglucosamine (GlcNAc) levels, in MDS/AML promoted M2-polarized subtype through the secretion of TGFβ1, which elevated PD-L1 expression and thereby impaired CD8+ T cell function. Our study provides insights into the mechanisms of selectively modifying specific glycans in bone marrow stroma cells may contribute to targeting strategies aimed at the tumor microenvironment.

DOI: https://doi.org/10.3324/haematol.2024.287091
Mechanobiol Med. 2023 Dec;1(2): 100013

Matrix stiffness-driven cancer progression and the targeted therapeutic strategy.

Rui Liang, Guanbin Song.

  Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells. The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads to deposition, contraction, and crosslinking of the stroma, promoting increased matrix stiffness in tumors. Matrix stiffness is critical to the progression of various solid tumors. As a mechanical factor in the tumor microenvironment, matrix stiffness is involved in tumor progression, promoting biological processes such as tumor cell proliferation, invasion, metastasis, angiogenesis, drug resistance, and immune escape. Reducing tissue stiffness can slow down tumor progression. Therefore targeting matrix stiffness is a potential option for tumor therapy. This article reviews the detailed mechanisms of matrix stiffness in different malignant tumor phenotypes and potential tumor therapies targeting matrix stiffness. Understanding the role and mechanisms of matrix stiffness in tumors could provide theoretical insights into the treatment of tumors and assist in the clinical development of new drug therapies.

Keywords:  Cancer progression; Cancer therapy; Immune escape; Matrix stiffness; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.mbm.2023.100013
Cell Rep. 2025 May 20. pii: S2211-1247(25)00504-2. [Epub ahead of print]44(6): 115733

Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity via the cGAS/STING pathway.

Ian-Ian Ng, Zhihua Zhang, Kaimin Xiao, Minjie Ye, Tingzhong Tian, Yaoji Zhu, Yuan He, Ling Chu, Haidong Tang.

  DNA damage profoundly affects cancer progression and immune cell function. While research primarily focuses on tumor cells, the effects of DNA damage on immune cells remain understudied. Here, we observe significant DNA damage in tumor-associated dendritic cells (TADCs), accompanied by the upregulation of the serine/threonine kinase WEE1, a crucial regulator of DNA damage repair. Interestingly, DNA damage also stimulates DC activation. WEE1 inhibition activates TADCs through the cGAS/STING pathway, increasing IL-12 and type I interferon expression, thus enhancing the antitumor immune response and improving tumor control. Additionally, WEE1 inhibition augments the efficacy of DC vaccines and synergizes with immune checkpoint blockade therapy. These findings highlight a pivotal role of WEE1 signaling in DNA damage repair in DCs within the tumor microenvironment, which in turn suppresses the antitumor immune response. Therefore, targeting WEE1 in DCs represents a promising approach to enhance T cell activation and improve the effectiveness of cancer immunotherapy.

Keywords:  CP: Cancer; CP: Immunology; DNA damage; WEE1; antigen presentation; cancer immunotherapy; dendritic cells

DOI:  https://doi.org/10.1016/j.celrep.2025.115733
Nat Commun. 2025 May 19. 16(1): 4652

Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.

Daniela Aviles-Huerta, Rossella Del Pizzo, Alexander Kowar, Ali Hyder Baig, Giuliana Palazzo, Ekaterina Stepanova, Cinthia Claudia Amaya Ramirez, Sara D'Agostino, Edoardo Ratto, Catarina Pechincha, Nora Siefert, Helena Engel, Shangce Du, Silvia Cadenas-De Miguel, Beiping Miao, Victor M Cruz-Vilchez, Karin Müller-Decker, Ilaria Elia, Chong Sun, Wilhelm Palm, Fabricio Loayza-Puch.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-59986-7
Cell Mol Immunol. 2025 May 23.

Adjusting the scope of natural killer cells in cancer therapy.

Zihen Shen, Xiangpeng Meng, Jai Rautela, Michael Chopin, Nicholas D Huntington.

  Natural killer (NK) cells have evolved to detect abnormalities in tissues arising from infection with pathogens, genomic damage, or transformation and respond rapidly to the production of potent proinflammatory and cytolytic mediators. While this acute proinflammatory response is highly efficient at orchestrating sterilizing immunity to pathogens in a matter of days, cellular transformation often avoids the innate detection mechanisms of NK cells. When cellular transformation results in malignancy, tumor cells and/or the tumor microenvironment can evolve additional mechanisms to circumvent NK cell responses, and cancer is now a dominant disease burden worldwide. Here, we review recent advances in our understanding of the combined relationship between malignancies and natural killer (NK) cells, learn from recent clinical efforts in therapeutically targeting natural killer (NK) cells in cancer and outline some emerging therapeutic concepts that aim to improve the innate immune response against cancer.

Keywords:  Cancer; Cytokines; Drug Development; Immunotherapy; Innate Immune cells; Natural Killer cell

DOI:  https://doi.org/10.1038/s41423-025-01297-4