bims-flamet 2025-07-06 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–07–06
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI

Plasticity of myeloid-derived suppressor cells in cancer and cancer therapy.
Orchestration of Tumor-Associated Macrophages in the Tumor Cell-Macrophage-CD8+ T Cell Loop for Cancer Immunotherapy.
Petiveria alliacea and Caesalpinia spinosa extracts reduce the generation of cancer-associated fibroblasts in a 3D platform representative of the tumor microenvironment.
From tumor immunity to precision medicine: the next step in B7-H3/CD276 research.
Recent advances in novel tumor immunotherapy strategies based on regulating the tumor microenvironment and immune checkpoints.
Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.
Interplay between tumor cells and immune cells of the colorectal cancer tumor microenvironment: Wnt/β-catenin pathway.
Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers.
Blocking immune checkpoint LAIR1 with antibody blockade or 3-in-1 CAR T cells enhances antitumor response.
Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.
Are connexin hemichannels playing any role in cancer?
The future belongs to those who believe in multiplex CAR T engineering.
Lipid metabolism in cancer stem cells: reprogramming, mechanisms, crosstalk, and therapeutic approaches.
Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.
Regulatory T cells poise the myeloid landscape after chemotherapy in lung tumors.
The type I collagen paradox in PDAC progression: microenvironmental protector turned tumor accomplice.
Sphingosine-1-phosphate stimulates colorectal cancer tumor microenvironment angiogenesis and induces macrophage polarization via macrophage migration inhibitory factor.
Correction to "Mild Acid-Responsive 'Nanoenzyme Capsule' Remodeling of the Tumor Microenvironment to Increase Tumor Penetration".
Near-Infrared-Triggered Nanodroplets for Imaging-Guided Macrophage-Mediated Cancer Immunotherapy.
Targeting CAF-specific metabolic pathways in breast cancer.
VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response.
Neutrophils in cancer: from immune defense to tumor promotion.

Oncol Res. 2025 ;33(7): 1581-1592

Plasticity of myeloid-derived suppressor cells in cancer and cancer therapy.

Jiajia Lv, Xiaoyou Zhong, Lin Wang, Weifei Fan.

  The tumor microenvironment (TME) is a complex and dynamic network comprised of tumor cells, surrounding cellular components, various signaling molecules, and the stroma. Myeloid-derived suppressor cells (MDSCs) are pivotal players in the immunosuppressive landscape of the TME, effectively hindering antitumor immune responses and facilitating tumor progression. Originating from pathologically activated myeloid precursors and relatively immature myeloid cells, MDSCs retain plasticity to further differentiate into other myeloid cells, such as macrophages or dendritic cells, which underpins their heterogeneity and adaptability in response to the TME. In this review, we delve into the plasticity of MDSCs in the tumor microenvironment and illuminate the underlying mechanisms that enable them to modulate immune responses. Furthermore, we explore the implications of MDSCs plasticity for cancer therapy, particularly its role in enhancing the efficiency of combination treatments.

Keywords:  Dendritic cells; Differentiation; Macrophages; Tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2025.060063
Int J Biol Sci. 2025 ;21(9): 4098-4116

Orchestration of Tumor-Associated Macrophages in the Tumor Cell-Macrophage-CD8+ T Cell Loop for Cancer Immunotherapy.

Lin He, Paul Kwong-Hang Tam, Chu-Xia Deng.

  The tumor microenvironment is densely populated with tumor-associated macrophages (TAMs), which exhibit various phenotypes at different stages of tumor progression. TAMs are highly plastic and intricately linked to the antitumor activity and functionality of CD8+ T cells. Tumor cells, TAMs and CD8+ T cells constitute a feedback loop that monitors the tumor immune surveillance. Modulation of several chief signaling pathways within TAMs can steer them towards either an immunoinflammatory or immunosuppressive state. This can be achieved indirectly through cancer therapies or by directly targeting TAMs. New detailed insights into the immunostimulatory reprogramming of TAMs inspire the design of novel combinatory strategies that can be extrapolated to bolster cancer immunotherapy.

Keywords:  CD8+ T cell; cancer immunotherapy; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.7150/ijbs.115932
Cancer Cell Int. 2025 Jul 02. 25(1): 243

Petiveria alliacea and Caesalpinia spinosa extracts reduce the generation of cancer-associated fibroblasts in a 3D platform representative of the tumor microenvironment.

María Camila Jimenez, Paola Lasso, Susana Fiorentino, Alfonso Barreto.

   BACKGROUND: The tumor microenvironment (TME) is a complex network of cellular and acellular participants, each of which contributes to ensuring tumor growth. Cancer-associated fibroblasts (CAFs) represent a key TME population that actively participates in stromal remodeling and metabolic coupling with tumors, significantly favoring both the process of carcinogenesis and the establishment of metastasis. Therefore, developing therapies that target CAFs constitute valuable therapeutic alternatives. However, efficiently modeling the generation of CAFs in the tumor microenvironment is challenging.
METHODS: We constructed a 3D structure of the tumor microenvironment (TME), which we refer to as "TME spheroids". These spheroids are composed of 4T1 murine breast cancer cells and 3T3 murine fibroblasts, allowing us to mimic the development of a cancer-associated fibroblast (CAF) phenotype. This novel 3D model serves as a platform for evaluating the impact of two natural extracts on TME interactions and their ability to impede tumor progression.
RESULTS: Using the TME-spheroid model, we tested the effects of two extracts on CAF generation: Anamu-SC obtained from Petiveria alliacea and P2Et from Caesalpinia spinosa. Both extracts disrupted the interaction between tumor cells and fibroblasts, reducing the ability of CAFs to support tumor growth and spread.
CONCLUSIONS: We found that the two extracts interfere with circuits that drive tumor-fibroblast crosstalk, attenuating the phenotype and functional activities associated with CAFs in this TME model.

Keywords:  3D culture systems; Cancer-associated fibroblasts; Drug screening; Natural therapies; Plant-based therapies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-03860-5
Med Rev (2021). 2025 Jun;5(3): 260-264

From tumor immunity to precision medicine: the next step in B7-H3/CD276 research.

Haolie Fang, Yuqian Liu, Gege Wang, Heng-Jia Liu.

  B7-H3 (CD276) is one of the immune checkpoint molecules at the forefront of cancer biology, plays a diverse role in immune regulation and cancer progression, while its immunosuppressive functions enable tumors to escape immune detection, its contribution to processes such as angiogenesis, metabolic reprogramming and chemoresistance underscores its broader impact on the tumor microenvironment (TME). These properties make B7-H3 an attractive target for cancer therapy. This perspective discusses the immune and non-immune related functions of B7-H3, the challenges in tapping its therapeutic potential.

Keywords:  B7-H3/CD276; cancer therapeutics; checkpoint inhibitors; immune evasion; tumor microenvironment

DOI:  https://doi.org/10.1515/mr-2025-0003
Front Immunol. 2025 ;16 1529403

Recent advances in novel tumor immunotherapy strategies based on regulating the tumor microenvironment and immune checkpoints.

Hanhui Jing, Yan Gao, Zongsheng Sun, Shanglong Liu.

  Tumor immunotherapy, a novel and rapidly progressing cancer treatment, has experienced remarkable advancements over recent years. It focuses on augmenting the patient's immune defenses and remodeling the immune microenvironment (IME) of tumors, rather than directly targeting malignant cells. The efficacy of immunotherapy relies substantially on multiple components within the tumor microenvironment (TME), extending beyond adaptive immunity alone. Immune cells within the TME play critical roles in both promoting immune surveillance and facilitating immune evasion. This complexity emphasizes the importance of immune checkpoint regulation in immunotherapeutic interventions. Therapeutically targeting specific immune cell subsets and metabolic pathways in combination treatments can transform an immunosuppressive TME into one that is immunologically activated, facilitating enhanced immune cell infiltration and consequently improving immunotherapy efficacy. Nevertheless, comprehensive research remains necessary to fully elucidate the mechanisms underlying TME interactions and immune checkpoint regulation, ultimately enabling more effective immunotherapeutic approaches.

Keywords:  cancer immunotherapy; immune cells; immune checkpoint; immunotherapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1529403
Sci Rep. 2025 Jul 01. 15(1): 20507

Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.

Rui Feng, Zilin Cui, Long Yang, Zirong Liu.

The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathways. Sphingosine 1-phosphate (S1P) is involved in immune regulation as a lipid metabolite. The role of S1P in the differentiation and metabolic regulation of tumor-associated macrophages is unknown. Meanwhile, the source of S1P in TME is not very clear. Our research found that hepatic stellate cells co-cultured with tumor cells could prompt macrophages to the M2 phenotype of TAM differentiation. It was further discovered that S1P activated peroxisome proliferator-activated receptor α (PPARα) by binding to S1P receptor 4 (S1PR4) of macrophages, upregulating lipid metabolism and inducing the TAM differentiation. Ultimately, tumor cells activated nuclear factor erythroid 2-related factor 2 (Nrf2) in hepatic stellate cells (HSCs), enhancing sphingosine kinase 1 (SphK1) expression and elevating S1P production and secretion. This study has demonstrated a possible interaction pathway among tumor cells, HSCs and macrophages. It has revealed that tumor cells activate the Nrf2/SphK1 pathway in HSCs to secrete S1P, which subsequently bound S1PR4, triggered PPARα activation, and drove macrophage polarization toward pro-tumor M2-type TAMs.

DOI: https://doi.org/10.1038/s41598-025-02588-6
Front Immunol. 2025 ;16 1587950

Interplay between tumor cells and immune cells of the colorectal cancer tumor microenvironment: Wnt/β-catenin pathway.

Aisha Saleh Janeeh, Khuloud Bajbouj, Bilal Rah, Eman Abu-Gharbieh, Mawieh Hamad.

  Colorectal cancer (CRC) is currently ranked as the third most frequent human cancer and the fourth leading cause of cancer-related deaths worldwide. Macrophages and immune cell subsets infiltrate the tumor microenvironment (TME) and modulate several cellular events and metabolic processes in CRC. Therefore, CRC-TME-infilitrating macrophages are thought to play a significant role in CRC progression, and could hence be potential therapeutic targets in CRC. Several lines of evidence suggest that the Wingless/Integrated (WNTs) family of signaling proteins plays a crucial role in CRC development and progression. Numerous studies have established that Wnt pathway signaling is involved in CRC-TME interaction; CRC-immune cell interaction in particular. Mounting experimental evidence point to the possibility that the TME in CRC can reciprocally modulate the Wnt/β-catenin pathway. Lastly, several studies have elaborated on the effect of drugs that disrupt the Wnt/β-catenin pathway as means of hindering CRC growth and progression. In this review, we discuss the multifaceted role of Wnt/β-catenin pathway in CRC and its TME as well as CRC-TME interactions. We also elaborate on the potential therapeutic utility of Wnt/β-catenin pathway-related targets in CRC.

Keywords:  Colorectal cancer; Wnt/β-catenin pathway; immune infiltration; macrophages; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1587950
Int J Biol Sci. 2025 ;21(9): 4187-4214

Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers.

Yilin Li, Jiaqi You, Zifang Zou, Guanghao Sun, Yuqing Shi, Yanbin Sun, Shun Xu, Xin Zhang.

The tumor microenvironment (TME) is dynamically shaped by interactions between tumor cells, immune cells, and stromal components. Among these, tumor-associated macrophages (TAMs) play dual roles in tumor progression. Exosomes are key mediators of intercellular communication and are crucial for modulating macrophage polarization. This review systematically summarizes the role of HIF-1α as the central regulator of tumor-derived exosomes under hypoxic conditions. Under endoplasmic reticulum stress (ERS), the STAT3 and PI3K/AKT/mTOR pathways activation is mediated by the inactivation of the Hsp90/Hippo pathway, which induces the expression of LncRNA HMMR-AS1 and specific miRNAs (e.g., miR-1246, let-7a, miR-301a-3p, etc.). Furthermore, the IRE1/PERK pathway regulates exosome secretion by carrying miR-23a-3p and miR-27a-3p or directly delivering PD-L1 protein, thus activating the PI3K/AKT pathway, inhibiting PTEN, and upregulating PD-L1 expression as well as increasing the M2 polarization of macrophages. This study also summarized the important matrices of exosomes' involvement in the interaction between tumor cells and macrophages in different systemic malignant tumors. Moreover, the bidirectional crosstalk between TAM-derived exosomes and other TME components (e.g., CD8+ T cells, fibroblasts) was also evaluated, which indicated their roles in immune evasion and metastasis. Further, engineering strategies, such as receptor-targeted exosomes and short palindromic repeats interference (CRISPRi)-based transcriptional silencing, were also discussed as emerging tools to enhance exosome specificity and therapeutic efficacy. This study proposes a roadmap for translating engineered exosomes into clinical immunotherapy regimens by integrating recent advances in spatial omics and artificial intelligence, and also addresses challenges in exosome isolation, stability, and biosafety.

DOI: https://doi.org/10.7150/ijbs.114222
J Clin Invest. 2025 Jul 01. pii: e184043. [Epub ahead of print]

Blocking immune checkpoint LAIR1 with antibody blockade or 3-in-1 CAR T cells enhances antitumor response.

Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy T Nguyen, Georges Abboud, Ruixuan Liu, Tianyi Liu, Avirup Chakraborty, Alicia Y Hou, Nicole A Petit, Muhammad Abbas, Robert W Davis, Janie Zhang, Christina Von Roemeling, Mohammed O Gbadamosi, Linchun Jin, Tongjun Gu, Tuo Lin, Pengchen Wang, Alfonso Pepe, Diego Ivan Pedro, Hector R Mendez-Gomez, Chao Xie, Aida Karachi, Frances Weidert, Dan Jin, Chenggang Wang, Kaytora Long-James, Elizabeth K Molchan, Paul Castillo, John A Ligon, Ashley P Ghiaseddin, Elias J Sayour, Maryam Rahman, Loic P Deleyrolle, Betty Ys Kim, Duane A Mitchell, W Gregory Sawyer, Jianping Huang.

  Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The Leukocyte-associated Immunoglobulin-like Receptor-1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1 → Factor XIII A (FXIII-A) → Collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout (Lair1-/-), antibody blockade (aLAIR1), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in one CAR construct) provides enhanced antitumor response. LAIR1 inhibition enhances peripheral and intratumoral CD8 memory T-cell populations, induces a phenotypic shift of M2-like Macrophages towards M1, and normalizes tumor collagen IV and structural components in the TME, facilitating effective tumor-T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1-/- or aLAIR1 was used alone or combined with CAR T cells or when the 3-in-1 CAR T cells were used solely in chemotherapy-radiation-PD-1 blockade-resistant tumor models. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.

Keywords:  Cancer immunotherapy; Macrophages; Oncology; T cells; Therapeutics

DOI:  https://doi.org/10.1172/JCI184043
Cell Commun Signal. 2025 Jul 01. 23(1): 307

Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.

Yiyi Shou, Ruiqi Liu, Hao Xiong, Keke Xu, Xiaoyan Chen, Luanluan Huang, Yitian Zhang, Hailong Sheng, Haibo Zhang, Yanwei Lu.

  Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.

Keywords:  Cancer metabolism; Cancer treatment; Metabolic reprogramming; Tumor immunogenicity; Urea cycle

DOI:  https://doi.org/10.1186/s12964-025-02328-3
Biochim Biophys Acta Mol Cell Res. 2025 Jun 28. pii: S0167-4889(25)00118-1. [Epub ahead of print]1872(7): 120013

Are connexin hemichannels playing any role in cancer?

Andrés Tittarelli, Kevin Calderón, María de Los Ángeles Esveile, Antonia B Abusleme, Mariana P Arbat, Mauricio A Retamal.

  Connexin (Cx) hemichannels have emerged as key regulators of both physiological and pathological processes. They exhibit a dual role in cellular function: while low-to-moderate activity supports cell-to-cell communication, excessive hemichannel opening can be detrimental, leading to cell death. In the context of cancer, the contribution of Cx hemichannels remains poorly defined. However, evidence from various models suggests that their activity may critically influence cancer progression. For example, Cx hemichannels mediate the release of signaling molecules such as ATP, which, upon conversion to adenosine, contributes to immunosuppression within the tumor microenvironment (TME). Notably, the activity of Cx hemichannels is modulated by several intracellular and extracellular factors-many of which are disrupted in tumors-suggesting that their regulatory dynamics in cancer may differ substantially from those under homeostatic conditions. This review aims to explore the potential roles of Cx hemichannels in shaping the TME, promoting immune evasion, and facilitating tumor progression. Given their putative relevance, future studies should focus on elucidating how cancer-associated alterations in regulatory mechanisms affect Cx hemichannel activity and whether such activity contributes to tumor aggressiveness. A clearer understanding of these processes may uncover novel therapeutic opportunities targeting Cx hemichannel regulation in oncology.

Keywords:  Cancer; Cell death; Cell proliferation; Connexins; Hemichannels; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120013
Cell Stem Cell. 2025 Jul 03. pii: S1934-5909(25)00230-9. [Epub ahead of print]32(7): 1031-1033

The future belongs to those who believe in multiplex CAR T engineering.

Laura Volta, Chiara F Magnani.

Toxicity and immune evasion have hindered the success of CAR T cells in HER2-positive solid tumors. In this issue of Cell Stem Cell, Hosking et al. present an iPSC-derived CAR T cell product engineered for tumor-selective targeting, resistance to the immunosuppressive tumor microenvironment, enhanced persistence and trafficking, and mitigation of antigen escape.

DOI: https://doi.org/10.1016/j.stem.2025.06.008
Cell Oncol (Dordr). 2025 Jun 30.

Lipid metabolism in cancer stem cells: reprogramming, mechanisms, crosstalk, and therapeutic approaches.

Haksoo Lee, Sujin Park, Jongwon Lee, Chaeyoung Lee, Hyunkoo Kang, JiHoon Kang, Jung Sub Lee, Eunguk Shin, HyeSook Youn, BuHyun Youn.

  Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs-including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism-such as inhibition of SCD1, CPT1A, and HMG-CoA reductase-have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.

Keywords:  Cancer stem cells; Chemoresistance; Lipid metabolism; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-025-01081-6
Adv Sci (Weinh). 2025 Jun 30. e04784

Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.

Jian-Gang Zhang, Xiao-Mei Zhang, Xi Wu, Cheng-Kai Zhou, Zhen-Zhen Liu, Xue-Yue Luo, Liang Zhang, Wei Chen, Yong-Jun Yang.

  The gut microbiota is increasingly recognized as a promising therapeutic target in cancer treatment. However, the specific mechanisms by which gut bacteria and their metabolites exert therapeutic effects in melanoma remain poorly understood. In this study, it is unexpectedly demonstrated that prophylactic supplementation with Limosilactobacillus reuteri exhibits significant tumor-suppressive properties, primarily mediated by its secreted metabolite, reuterin. This metabolite induces trained immunity through macrophage metabolic reprogramming, thereby enhancing antitumor immune responses. Mechanistically, this process involves stabilizing HIF-1α via the AHR-ROS signaling pathway, enhancing glycerophospholipid metabolism, and elevating arachidonic acid levels, thereby amplifying the trained immunity response. Similar to reuterin, arachidonic acid also induces trained immunity and facilitates macrophage-mediated tumor cell killing. To enhance its therapeutic efficacy, reuterin is encapsulated in covalent organic frameworks (COFs). COF-Reuterin demonstrates superior effects in tumor-associated macrophages (TAMs), remodulating intratumor bacteria and directly facilitating tumor cell killing. Notably, COF-Reuterin demonstrates superior therapeutic efficacy compared to cisplatin. Furthermore, COF-Reuterin reprogrammed TAMs from an M2 to an M1 phenotype, increasing CD8+ T cell infiltration and decreasing myeloid-derived suppressor cells (MDSCs), reshaping the immunosuppressive tumor microenvironment. These findings highlight the potential of probiotics and their metabolites in the metabolic reprogramming of TAMs, offering a promising cancer therapeutic approach.

Keywords:  Limosilactobacillus reuteri; intratumor bacteria; melanoma; reuterin; trained immunity; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202504784
Cancer Immunol Res. 2025 Jul 02.

Regulatory T cells poise the myeloid landscape after chemotherapy in lung tumors.

Eléonore Weber-Delacroix, Marylou Panouillot, Marie Laviron, François Lanthiez, Tristan Philippe, Sandrine Barthélémy, Solène Fastenackels, Armanda Casrouge, Benoit L Salomon, Ingrid Sassoon, Jeremy Baudhuin, Ilaria Onorati, Marianne Kambouchner, Nahla Cucherousset, Christophe Combadière, Boris Duchemann, Marie-Caroline Dieu-Nosjean, Alexandre Boissonnas.

Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. While Tregs are well known for their immune suppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. We showed in human and mouse lung cancer, that chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward a pro-inflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the pro-inflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the pro-inflammatory signature of the MPs and improved survival in the mouse model. Targeting the crosstalk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0103
J Transl Med. 2025 Jul 04. 23(1): 744

The type I collagen paradox in PDAC progression: microenvironmental protector turned tumor accomplice.

Qian Li, Cheng Yang, Junqiang Li, Ronglin Wang, Jie Min, Yang Song, Haichuan Su.

Type I collagen (Collagen I, Col I), a principal component of the tumor extracellular matrix (ECM) that accounts for 80% of total ECM collagen, has emerged as a crucial factor in tumor biology. Recent research has found that Col I has influenced tumor growth, invasion, migration, and prognosis by forming a physical barrier and interacting with components in the tumor microenvironment (TME). Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity, which significantly impacts the biology of the disease and its resistance to treatment. As research on the influence of ECM on tumor behavior progresses, the role of Col I in tumor occurrence and development has also been gradually expounded. Unlike the pro-tumorigenic role caused by excessive deposition in other cancers, PDAC features a dense stroma with spatial heterogeneity, where Col I deposition exhibits paradoxical pro- and anti-tumor effects: Cancer-associated fibroblasts secrete heterotrimeric Col I (α1/α1/α2), which initially suppresses tumor growth by recruiting M1 macrophages, while tumor cells produce homotrimeric Col I (α1/α1/α1, 2-3% of total Col I) to promote immune evasion via CXCL5 secretion and CD8+ T cell reduction. Mechanistically, Col I activates TGF-β/SMAD3 signaling to drive epithelial-mesenchymal transition (EMT) and enhances matrix stiffness, increasing tumor cell migration by 60-80% in 3D cell culture models. Thus, understanding the complex interactions between Col I and other microenvironmental components may enhance its anti-tumor action while suppressing its pro-tumor activity, potentially improving PDAC patients' survival. In this review, we discuss the current research progress regarding the function of Col I in PDAC tumors and summarize its contributions to PDAC progression, thus providing a basis for follow-up research and potential targets for cancer treatment.

DOI: https://doi.org/10.1186/s12967-025-06778-8
Front Immunol. 2025 ;16 1564213

Sphingosine-1-phosphate stimulates colorectal cancer tumor microenvironment angiogenesis and induces macrophage polarization via macrophage migration inhibitory factor.

Fang Wu, Zhaode Feng, Xuan Wang, Yingcong Guo, Bingcong Wu, Shuheng Bai, Ning Lan, Min Chen, Juan Ren.

   Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy with extensive reprogramming of sphingolipid metabolism. However, the role and mechanisms of sphingosine-1-phosphate (S1P), a key bioactive molecule in sphingolipid metabolism, remain insufficiently characterized. Therefore, this study integrated multi-omics data to elucidate the characteristics and functions of S1P within the tumor microenvironment (TME) and investigated its role in angiogenesis through in vitro experiments.
Methods: We used bulk RNA sequencing data sets (RNA-seq) to study the prognostic value and clinicopathological characteristics of the increased synthesis of S1P. In order to elucidate the contribution of S1P to the complexity of the tumor microenvironment, we employed intercellular communication analysis and functional enrichment analysis at the single-cell transcriptome (scRNA-seq) level. The expression of Sphingosine kinase 1 (SPHK1) in human tissues was verified by immunohistochemical staining (IHC). Then, we inhibited the synthesis of S1P by suppressing SPHK1 at the cellular level to explore the changes in the pro-angiogenic function of tumor cells and M2-like macrophages, as well as the direction of macrophage polarization.
Results: S1P activity is elevated in the TME of CRC, and the increased synthesis of S1P suggests poor prognosis and early metastasis. intercellular communication analysis indicates that high S1P epithelial cells can promote angiogenesis and influence the polarization of tumor-associated macrophages (TAMs) through the macrophage migration inhibitory factor (MIF) pathway. TAMs were grouped according to gene expression patterns, in which, PCLAF+ cluster TAMs showed significantly high S1P activity, contributing to tumor growth and angiogenesis. IHC demonstrated elevated levels of SPHK1 protein expression in CRC tumor tissues. Inhibition of the synthesis of S1P in tumor cells and macrophages suppressed macrophage M2 polarization levels and reversed the pro-angiogenic phenotype by inhibiting VEGFA protein expression. Spatial transcriptomics revealed a correlation between the distribution of SPHK1 and M2-like macrophage.
Conclusions: By integrating multi-omics data and further cellular experiments, we propose that inhibition of S1P may play an important role in inhibiting angiogenesis and reversing M2-type macrophage polarization, demonstrating its anti-tumor efficacy in CRC.

Keywords:  angiogenesis; colorectal cancer; scRNA-seq; sphingosine-1-phosphate; tumor-associated macrophages polarization

DOI:  https://doi.org/10.3389/fimmu.2025.1564213
ACS Appl Mater Interfaces. 2025 Jun 30.

Correction to "Mild Acid-Responsive 'Nanoenzyme Capsule' Remodeling of the Tumor Microenvironment to Increase Tumor Penetration".

Hanchun Yao, Xiaofang Guo, Huijuan Zhou, Jinjin Ren, Ying Li, Songchao Duan, Xiaobao Gong, Bin Du.

DOI: https://doi.org/10.1021/acsami.5c11886
Small Methods. 2025 Jul 01. e2401679

Near-Infrared-Triggered Nanodroplets for Imaging-Guided Macrophage-Mediated Cancer Immunotherapy.

Junxi Yi, Meenakshi Chauhan, Yang Zhao, Yun-Sheng Chen.

  Immunotherapy has transformed cancer treatment; however, solid tumors often evade checkpoint blockade by co-opting tumor-associated macrophages (TAMs) and creating a hypoxic, immunosuppressive tumor microenvironment. Here, we report a laser-triggered theranostic nanodroplet capable of simultaneously remodeling the tumor microenvironment and visualizing therapeutic responses in real-time. These double-emulsion perfluorocarbon droplets encapsulate clinically translatable components: a toll-like receptor-7/8 agonist and near-infrared indocyanine green dye. Upon activation by a near-infrared laser pulse, the nanodroplets transform into echogenic microbubbles, facilitating imaging and targeted therapeutic release. In a mouse model of human triple-negative breast cancer, a single nanodroplet injection followed by periodic illumination repolarized M2-like TAMs into an M1 phenotype, alleviated intratumoral hypoxia, and synergistically anti-programmed-cell-death-protein-1 therapy, resulting in a six-fold reduction in tumor size compared to checkpoint blockade alone. Concurrent non-invasive dual-modal ultrasound and multispectral photoacoustic imaging tracked nanodroplet biodistribution, macrophage recruitment, and oxygen saturation longitudinally, enabling real-time guidance of dosing schedules without biopsy. The nanodroplets demonstrated greater than 60% loading efficiency, minimal hemolysis, and high biocompatibility in vitro. By coupling spatiotemporally controlled immunomodulation with quantitative imaging, this platform addresses critical challenges in treating refractory solid tumors and provides a roadmap for adaptive, image-guided combination immunotherapy.

Keywords:  M1 macrophage polarization; hypoxia; immunotherapy; nanodroplets; photoacoustic and ultrasound imaging; theranostics; tumor microenvironment

DOI:  https://doi.org/10.1002/smtd.202401679
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 01.

Targeting CAF-specific metabolic pathways in breast cancer.

Alaa Khalaf Bediwi, Ahmed Hjazi, Mundher Kedhem, Ali G Alkhathami, RenukaJyothi S, Priya Priyadarshini Nayak, Amrita Pargaien, Udaybir Singh, Fathi Jihad Hammady, Salah Abdulhadi Salih.

  Breast cancer (BC) cells are distinguished by their capacity to reconfigure metabolism to support rapid growth and survive in hypoxic, nutrient-deficient environments. In the breast tumor microenvironment (TME), metabolic changes-including the Warburg effect, modifications in Krebs cycle intermediates, and adjusted oxidative phosphorylation-are closely associated with the dynamic signaling between tumor cells and stromal elements. Cancer-associated fibroblasts (CAFs), a diverse and adaptable group inside the stroma, significantly influence metabolic pathways, including those regulating glucose, amino acid, and lipid metabolism. Recent research underscores that the metabolic interaction between BC cells and CAFs not only promotes tumor growth and invasion but also facilitates treatment resistance. This review is aimed at consolidating the existing data on the metabolic interactions between BC cells and CAFs, highlighting molecular mechanisms and pathways that could represent potential targets for future therapies.

Keywords:  Breast cancer; Cancer-associated fibroblasts; Metabolic pathways; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00210-025-04390-7
Cell Rep. 2025 Jun 27. pii: S2211-1247(25)00664-3. [Epub ahead of print]44(7): 115893

VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response.

Dhanya K Nambiar, Sainiteesh Maddineni, Jimpi Langthasa, Hongbin Cao, Vignesh Viswanathan, Junyan Liu, Md Tauhidul Islam, Nishant Mehta, Jessica Frank, Alexander Real, Tia Cheunkarndee, Eyiwunmi Eghonghon Laseinde, Bhushan Dharmadhikari, Dipti Thakkar, Jerome D Boyd-Kirkup, Andrey Finegersh, Vasu Divi, John B Sunwoo, John Aleman, Xiao-Jing Wang, Christina Kong, Lei Xing, Jennifer R Cochran, Quynh-Thu Le.

  Radiotherapy (RT) is a key treatment for solid neoplasms like head and neck cancer (HNC), but it can also activate and recruit immunosuppressive myeloid cells, causing treatment failure. In this study, we examine the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) on myeloid cells during RT. We discovered high VISTA expression on myeloid cells in the tumor microenvironment (TME) of both murine and human HNC, with RT increasing VISTA+ myeloid cells in the TME and circulation. Compared to VISTA+/+ mice, VISTA-/- mice showed improved tumor control with RT, with their macrophages and neutrophils exhibiting antitumorigenic properties on sc-RNA-seq analysis, especially with RT. Combining anti-VISTA antibodies (active or silent Fc) with RT (fractionated or ablative) significantly decreased tumor volume compared to either treatment alone in multiple preclinical models (HNC, breast cancer, and colorectal cancer), enhancing systemic antitumor immune response with augmented intra-tumoral T cell function through myeloid repolarization. Targeting VISTA could improve the efficacy of RT.

Keywords:  CP: Cancer; CP: Immunology; HNSCC; MDSC; VISTA; antitumor immune response; immune checkpoint; radiotherapy

DOI:  https://doi.org/10.1016/j.celrep.2025.115893
Cancer Biol Med. 2025 Jul 02. pii: j.issn.2095-3941.2025.0023. [Epub ahead of print]

Neutrophils in cancer: from immune defense to tumor promotion.

Zhen Wang, Hanwen Hu, Yunjia Bao, Liwei Pang, Chenghui Yang.

  Neutrophils are the protagonists of the host immune response, possessing potent antimicrobial and inflammatory capacities. The neutrophil reservoir as well as the development, mobilization, chemotaxis, pro-inflammatory activity, and clearance of neutrophils are strictly regulated to prevent inflammation-induced tissue damage. Inflammation pervades almost every type of cancer. However, there is growing awareness that although the tumor microenvironment has the capacity to recruit neutrophils, the functions are diverse and include roles other than that of sentinels in cancer. This review highlights the heterogeneity of neutrophils in tumors, discusses the dual role of neutrophils as angels and demons in tumorigenesis, invasion, and metastasis, and examines the potential of neutrophils as targets in clinical therapy.

Keywords:  Neutrophil; cancer; diversity; inflammation; metastasis; tumor microenvironment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0023