bims-flamet 2025-10-12 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–10–12
thirty papers selected by
Peio Azcoaga, Biodonostia HRI

Macrophage repolarization by immune checkpoint blockade drives T cell engagement in the tumor microenvironment.
B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors.
Microenvironment of Solid Tumors.
Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.
Imperial strategy of cancer cells through mitochondrial transfer.
Arginine Competition in Tumor Microenvironment: A Potential Target for Cancer Therapy.
Immunopathology of Glioblastoma.
Emerging mechanisms of triple-negative breast cancer radioresistance: Interplay between cancer cell mechanisms and the tumor immune microenvironment.
The differential regulation of the urea cycle in tumors goes awry.
STRESS-INDUCED MODULATION OF THE TUMOR MICROENVIRONMENT: MECHANISMS AND IMPLICATIONS FOR CANCER PROGRESSION.
Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy.
Penetrative biomimetic nanovehicle boosts immunotherapy in triple-negative breast cancer via SOS1 blockade.
Angiogenesis and Immunosuppressive Niche in Hepatocellular Carcinoma: Reshaping Vascular - Immune Axis to Potentiate antiPD - 1/PD - L1 Therapy.
IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice.
Positive and negative roles of myeloid cells in cancer immunotherapy.
The role of dysbiosis in shaping host immunity in endometrial cancer development.
Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.
CAR-ving a Path: Metalloprotease-Engineered CAR T Cells Tunnel through Solid Tumors.
The Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions.
Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy.
The physiological and pharmaceutical roles of MCTs and other ingredients in intravenous emulsions containing omega-3 enriched fish oil designed to mitigate cytokine release syndrome.
Tumor cells upregulate CCL22 in a STING-dependent manner in response to paracrine factors released by STING-activated myeloid cells and type I interferons.
Microbial metabolites and their influence on the tumor microenvironment.
Bacteria biohybrids integrating anticancer peptide-loaded nanoparticles for tumor immunotherapy through pyroptosis activation.
Metabolite to Modifier: Lactate and Lactylation in the Evolution of Tumors.
Decoding immune low-response states in ovarian cancer: insights from single-cell and spatial transcriptomics for precision immunotherapy.
Spatiotemporally Controlled Nanomicelles for Synergistic Phototherapy and Immune Reprogramming in Triple-Negative Breast Cancer.
Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.
Exosomal non-coding RNAs: mediators of crosstalk between cancer and cancer stem cells.
Immune-modulatory effects of low-dose radiotherapy through macrophage polarization and transcriptional rewiring in triple-negative breast cancer.

iScience. 2025 Oct 17. 28(10): 113538

Macrophage repolarization by immune checkpoint blockade drives T cell engagement in the tumor microenvironment.

Tina Kwok, Ildefonso A Silva-Junior, Sara Korpe, Haidong Dong, Jessica N Lancaster.

  Immunotherapy combinations can improve patient outcomes, yet the interactions within the tumor microenvironment (TME) that drive therapeutic synergy are poorly understood. Tumor establishment drives monocyte recruitment and differentiation into tumor-associated macrophages (TAMs), which have essential roles in coordinating immune responses and are thus attractive targets for therapeutic modulation. In a murine model of combination anti-programmed cell death protein 1 (PD-1) and its ligand (anti-PD-L1) checkpoint blockade, tumor control was associated with increased infiltration of CD8+ T cells and M1-like repolarization of TAMs. Live-cell imaging of the tumor microenvironment revealed close contacts between tumor-infiltrating CD8+ T cells and TAMs, in which the extent of the contact interfaces increased with combination immunotherapy. Treatment with anti-PD-L1 was able to increase macrophage expression of pro-inflammatory factors and phagocytic activity, suggesting a role for TAMs in reactivating CD8+ T cells in the TME. However, co-treatment with anti-PD-1 was ultimately necessary for tumor control, indicating the need for combination targeting of the TME.

Keywords:  Cancer; Immunology; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2025.113538
Cancer Metastasis Rev. 2025 Oct 11. 44(4): 77

B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors.

Lena Jansen, Judith Wienke, Ronja Molkenbur, Claudia Rossig, Ramona Meissner.

  B7 homolog 3 (B7-H3, CD276) has emerged as a promising target for chimeric antigen receptor (CAR) T cell therapy, with limited expression in normal tissues and high level cell-surface expression across various tumor types. Clinical studies are ongoing, with a focus on pediatric cancers. As an immune checkpoint molecule of the B7-CD28 family, B7-H3 has a proposed immune-modulatory role, though the precise nature of B7-H3-mediated cell interactions and functional contributions to immune responses are contradictory and likely context-dependent. Within tumors, B7-H3 is expressed also on non-tumor cell types in the tumor microenvironment (TME), including myeloid immune cells, endothelial cells of abnormal vasculature and cancer-associated fibroblasts. Consequently, CAR T cells directed against B7-H3 will not only target tumor cells but also components of the TME, which will affect the nature and outcome of B7-H3-targeted therapeutic immune responses. Here we review the expression of B7-H3 protein in pediatric solid tumors and in various cell types known to infiltrate the TME of solid tumors. On this background, we discuss the potential of B7-H3-targeted CAR T cells to reshape the TME and the key challenges and future directions to improve B7-H3-targeted CAR T cell therapy for pediatric patients with solid cancers.

Keywords:  B7-H3; CAR T cells; CD276; Immune checkpoints; Pediatric solid cancers; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10555-025-10294-y
Front Biosci (Landmark Ed). 2025 Sep 23. 30(9): 36940

Microenvironment of Solid Tumors.

Tatyana V Korneenko, Nikolay B Pestov, Mikhail I Shakhparonov, Nickolai A Barlev.

  The tumor microenvironment (TME) plays a fundamental role in tumor progression. Cancer cells interact with their surroundings to establish a supportive niche through structural changes and paracrine signaling. Cells around transformed tumor cells contribute to cancer development, while infiltrating immune cells in this aggressive TME often become exhausted. Solid tumors, especially the most invasive types such as pancreatic ductal adenocarcinoma, are notably stiff mechanically, with cross-linking enzymes significantly affecting the survival of cancer cells in both primary tumors and metastatic sites. In this review, we highlight recent key contributions to the field, focusing on single-cell sequencing of stromal cells, which are increasingly seen as highly heterogeneous yet classifiable into distinct subtypes. These new insights enable the development of effective co-treatment approaches that could significantly enhance current and novel therapies against the most aggressive cancers.

Keywords:  cancer; cancer-associated cells; desmoplasia; extracellular matrix; metastasis

DOI:  https://doi.org/10.31083/FBL36940
Mol Cancer. 2025 Oct 08. 24(1): 247

Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  Metabolic reprogramming is one of the fundamental characteristics of thyroid cancer (TC), which meets its energy and biosynthetic demands through mitochondrial dysfunction, glycolysis activation, lipid metabolism imbalance, and glutamine dependency, thereby promoting metastasis and reshaping the immune microenvironment. Exosomes, as extracellular vesicles, play a crucial role in TC by delivering bioactive molecules such as proteins, lipids, and nucleic acids. In the tumor microenvironment (TME) of TC, exosomes secreted by both tumor and non-tumor cells interact with each other, driving metabolic reprogramming and forming a bidirectional regulatory network. This significantly alters the biological characteristics of TC cells, including proliferation, invasion, metastasis, angiogenesis, and the acquisition of drug resistance and immune tolerance, ultimately influencing the process of immune escape in TC. This review systematically summarizes how exosomes in the TME of TC promote tumor progression through metabolic reprogramming, providing new diagnostic and therapeutic strategies for patients with locally advanced, radioiodine-refractory TC.

Keywords:  Exosomes; Immune escape; Metabolic reprogramming; Thyroid cancer; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02470-z
Mol Oncol. 2025 Oct 05.

Imperial strategy of cancer cells through mitochondrial transfer.

Takamasa Ishino, Yosuke Togashi.

  Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer-associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro-tumorigenic activity. Our group has identified mitochondrial 'hijack' from cancer cells to tumor-infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages.

Keywords:  cancer‐associated fibroblast; mitochondrial transfer; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.70142
Med Res Rev. 2025 Oct 07.

Arginine Competition in Tumor Microenvironment: A Potential Target for Cancer Therapy.

Junlei Zhang, Sijie Wang, Huihui Liu, Lihua Luo, Jian You.

  Arginine is critical in biosynthesis, energy generation, cell proliferation, and immune regulation. In the tumor microenvironment (TME), due to limited supply and high consumption, the competition for arginine is extremely fierce. It always ends up with the victory of tumor cells and immunosuppressive cells, which leads to the arginine deficiency for anti-tumor immune cells, resulting in immune tolerance of tumors. Therapies based on arginine metabolism have been extensively studied. An arginine deprivation therapy has been developed as the tumor progression relies on arginine support. To reverse the arginine shortage of anti-tumor immune cells in TME, supplying arginine to enhance immune therapy has been proposed. Achieving the optimal antitumor effects of these two opposed therapies requires a better understanding of arginine metabolism in TME. In this review, we compared the transport, synthesis, and metabolism of arginine in tumor cells and various immune cells, and proposed key processes that may serve as potential therapeutic targets. In addition, for the two therapies for arginine, deprivation and supplementation, the recent research of them was discussed, and the relevant clinical trials were collected and summarized, which might provide reliable references for the further study and application of arginine-based therapies.

Keywords:  arginine metabolism; clinical trials; immune therapy; nutritional oncology; tumor microenvironment

DOI:  https://doi.org/10.1002/med.70015
Annu Rev Pathol. 2025 Oct 08.

Immunopathology of Glioblastoma.

Jiabo Li, James L Ross, Dolores Hambardzumyan, Daniel J Brat.

Glioblastoma (GBM), the most frequent and malignant primary brain tumor, is characterized by a highly diverse and profoundly immunosuppressive tumor microenvironment (TME) that provides an unconstrained environment for tumor progression and significantly complicates therapeutic interventions. Despite advances in immunotherapeutic approaches, such as chimeric antigen receptor T cell and immune checkpoint inhibitors, efficacy remains limited due to the complexity of the GBM TME and robust immune evasion mechanisms. In this review, we elucidate the intricate interplay among cellular components within the TME that lead to this immunosuppressive state, including tumor-associated macrophages/microglia, myeloid-derived suppressor cells, regulatory T cells, and glioma stem cells, as well as other critical elements that contribute to TME complexity, such as the severe hypoxia associated with central necrosis, the blood-brain barrier, and the extracellular matrix. This review also highlights mechanisms of immune evasion and recent immunotherapeutic approaches along with their biologic rationale, underscoring the need for integrated therapeutic strategies that both target immunosuppressive elements and enhance immune activation.

DOI: https://doi.org/10.1146/annurev-pathmechdis-042524-025950
Cancer Treat Rev. 2025 Sep 28. pii: S0305-7372(25)00148-3. [Epub ahead of print]140 103026

Emerging mechanisms of triple-negative breast cancer radioresistance: Interplay between cancer cell mechanisms and the tumor immune microenvironment.

Ana Canha-Borges, Bárbara Nunes, Sofia Torres Quintas, Joana Paredes, Lydia Meziani, Michele Mondini, Maria José Oliveira, Eric Deutsch, Flávia Castro.

  Breast cancer is the most common and deadliest cancer in women worldwide. Among the distinct subtypes, triple negative breast cancer (TNBC) stands out as the most aggressive one, showing high resistance to treatments, including chemotherapy, radiotherapy, and immunotherapy. Radiotherapy remains a standard treatment for TNBC, offering significant benefits in reducing local relapse. However, resistance to radiotherapy remains a major challenge, limiting its effectiveness and narrowing treatment options. Radioresistance in TNBC is driven by both tumor cell-intrinsic mechanisms and tumor immune microenvironment (TIME)-related processes. Intrinsically, TNBC cells employ strategies such as enhanced DNA damage repair mechanisms, tumor hypoxia adaptation, activation of survival pathways, and the contribution of cancer stem cells and extracellular vesicles. Extrinsically, the TIME can further fuel resistance by recruiting immunosuppressive cells (myeloid-derived suppressor cells, macrophages, neutrophils and regulatory T cells) and by releasing factors that impair the antitumor immune response mediated by T cells and natural killer cells. This review explores the dual contribution of cancer cell-specific mechanisms and TIME dynamics in TNBC radioresistance. We further discuss the paradoxical role of the immune system in radioresponse, highlighting emerging combination therapies, and address the challenges of translating these strategies into clinical applications. Ongoing clinical trials targeting radioresistance are also summarized, reflecting the latest efforts to enhance therapeutic outcomes for TNBC patients.

Keywords:  Breast cancer; Immune system; Radiotherapy; Resistance mechanisms; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctrv.2025.103026
Biochem Pharmacol. 2025 Oct 07. pii: S0006-2952(25)00630-6. [Epub ahead of print] 117365

The differential regulation of the urea cycle in tumors goes awry.

Ahmed M Abou-Shanab, Mennatallah A Khedr, Sandro Matosevic.

  Cancer cells exhibit significant metabolic reprogramming to support their rapid proliferation and survival. Most of the normal and cancer cells are glucose avid, which is metabolized, producing lactate (the Warburg effect). The urea cycle (UC) is traditionally associated with nitrogen detoxification in the liver. UC is boosted in normally proliferating cells; however, disruptions in UC activity are frequently observed in various cancers, leading to altered nitrogen metabolism and the accumulation of ammonia. This review covers the intricate relationship between the UC and cancer progression. We discuss how UC dysregulation contributes to tumorigenesis by promoting pyrimidine synthesis, altering amino acid metabolism, and modulating the tumor microenvironment. Additionally, we explore the impact of ammonia accumulation on cancer cell proliferation, stemness, and immune evasion. Understanding the metabolic rewiring of the UC in cancer offers novel therapeutic opportunities. Targeting UC enzymes or ammonia detoxification pathways may provide effective strategies to inhibit tumor growth and enhance the efficacy of immunotherapeutics.

Keywords:  Ammonia; Cancer; Metabolism; Tumor microenvironment; Urea cycle

DOI:  https://doi.org/10.1016/j.bcp.2025.117365
Exp Oncol. 2025 Oct 07. 47(2): 127-142

STRESS-INDUCED MODULATION OF THE TUMOR MICROENVIRONMENT: MECHANISMS AND IMPLICATIONS FOR CANCER PROGRESSION.

V Chekhun, T Burda, O Mushii, A Pavlova, T Borikun, T Zadvornyi, N Lukianova.

Chronic stress is one of the key exogenous factors that can significantly affect tumor cell biology by disrupting the regulation of the tumor microenvironment (TME), thereby promoting the manifestation of the malignant process. Activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system induced by stressors leads to the secretion of glucocorticoids and catecholamines, which contribute to the deregulation of microenvironmental components that determine the aggressiveness of malignant neoplasms. This review systematizes the current views on the impact of stress-induced signals on the immune, stromal, vascular, and metabolic components of the TME and analyzes their contribution to the formation of an aggressive tumor phenotype. Particular attention is given to the interplay between neurohumoral stress, the gut, and the intratumoral microbiome, forming a complex networked environment supporting tumor progression. Advancing the understanding of molecular interactions between stress mediators and cellular elements of the TME will provide a foundation for developing innovative therapeutic strategies targeting not only the tumor itself but also minimizing the adverse effects of stress on individual components of the TME.

DOI: https://doi.org/10.15407/exp-oncology.2025.02.127
Acta Pharm Sin B. 2025 Sep;15(9): 4476-4496

Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy.

Haojun Wang, Yang Yu, Runze Li, Huiru Zhang, Zhe-Sheng Chen, Changgang Sun, Jing Zhuang.

  The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features-the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-κB, cGAS-STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment. Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment-particularly SASP-holds great potential for advancing future anti-tumor therapies.

Keywords:  Aging; Anti-tumor immunotherapy; Immunoregulatory mechanisms; Immunosenescence; Immunotherapy; PD-L1; Senescence-associated secretory phenotype; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2025.07.022
Asian J Pharm Sci. 2025 Oct;20(5): 101064

Penetrative biomimetic nanovehicle boosts immunotherapy in triple-negative breast cancer via SOS1 blockade.

Jiaxin Zhang, Peng Xian, Chao Wang, Xier Pan, Yaoyao Du, Yunrong Nan, Qing Pu, Linghui Zou, Donovan Green, Shuting Ni, Kaili Hu.

  Immunotherapy of triple-negative breast cancer (TNBC) is significantly hindered by the immunosuppressive tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), which constitute the predominant infiltrating immune cell type in TNBC, represent a critical target for "turning off" immunosuppressive TME. Despite numerous ongoing clinical trials, current strategies exhibit limited efficacy in overcoming immunosuppressive TME. Interestingly, regulation of son of sevenless 1 (SOS1), which is overexpressed in TNBC patients, shows promising potential for TAM repolarization. Herein, we developed a biomimetic liposomal platform (CCM/Cil-lipo@TD), which integrates cilengitide (Cil)-functionalized breast cancer cell membranes (CCM) to co-deliver tetrandrine (TET) and low-dose docetaxel (DTX) for TNBC therapy. This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death (ICD)-mediated dendritic cell (DC) maturation, thereby reshaping the highly immunosuppressive TME in TNBC. Critically, the low-density Cil-anchored, CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems, achieving deep intratumoral accumulation of therapeutic payloads. Mechanistically, the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2 (protumor) toward TAM1 (antitumor). Furthermore, SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME, as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells. The CCM/Cil-lipo@TD exerted superior tumor inhibition (82.9 %) in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis. Taken together, the Cil-engineered, cell membrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.

Keywords:  Cilengitide; Docetaxel; Liposome; Son of sevenless 1; Tetrandrine; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.ajps.2025.101064
Cancer Manag Res. 2025 ;17 2245-2259

Angiogenesis and Immunosuppressive Niche in Hepatocellular Carcinoma: Reshaping Vascular - Immune Axis to Potentiate antiPD - 1/PD - L1 Therapy.

Wei Li, Gen-Cong Li, Cui-Song Luo, Qiang-Feng Yu, Min Cui.

  Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death worldwide, and its complex tumor microenvironment (TME) presents significant challenges for the treatment of this disease. In recent years, tumor immunotherapy has emerged as one of the most successful strategies in cancer treatment, especially for advanced HCC. Programmed cell death protein-1 (PD-1) inhibitors have moderate efficacy as monotherapies for HCC. Tumor angiogenesis, a crucial factor in tumor growth and proliferation, plays a pivotal role in the immune regulation of HCC. The vascular and immune microenvironments of solid tumors engage in dynamic reciprocal crosstalk, forming a complex vascular-immune axis that critically shapes antitumor immune responses and drives therapy resistance. The high degree of angiogenesis observed in HCC leads to abnormal vascular structure and function, which not only promotes tumor growth but also induces hypoxia and acidosis within the TME, thereby suppressing the immune response through various mechanisms. Given the regulatory role of tumor blood vessels in the immune system, the integration of antiangiogenic therapy into current immunotherapy approaches provides a novel treatment option. This integration involves the inhibition of tumor angiogenesis, improvements in the TME, and enhancements of the immune response, among other mechanisms. This review summarizes the angiogenic mechanisms of HCC, the clinical applications of immunotherapy and the regulatory effects of angiogenesis on the immune response in HCC.

Keywords:  PD-1/PD-L1; angiogenesis; hepatocellular carcinoma; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.2147/CMAR.S537930
J Clin Invest. 2025 Oct 07. pii: e193945. [Epub ahead of print]

IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice.

Yue Deng, Xixi Liu, Xiao Yang, Wenwen Wei, Jiacheng Wang, Zheng Yang, Yajie Sun, Yan Hu, Haibo Zhang, Yijun Wang, Zhanjie Zhang, Lu Wen, Fang Huang, Kunyu Yang, Chao Wan.

  The immunosuppressive tumor microenvironment (TME) drives radioresistance, but the role of γδ T cells in regulating radiosensitivity remains incompletely understood. In this study, we found that γδ T cell infiltration in the TME substantially increased after radiotherapy and contributed to radioresistance. Depletion of γδ T cells enhanced radiosensitivity. Single-cell RNA sequencing revealed that γδ T cells in the post-radiotherapy TME were characterized by the expression of Zbtb16, Il23r, and Il17a, and served as the primary source of IL-17A. These γδ T cells promoted radioresistance by recruiting myeloid-derived suppressor cells and suppressing T cell activation. Mechanistically, radiotherapy-induced tumor cell-derived microparticles containing dsDNA activated the cGAS-STING/NF-κB signaling pathway in macrophages, upregulating the expression of the chemokine CCL20, which was critical for γδ T cell recruitment. Targeting γδ T cells and IL-17A enhanced radiosensitivity and improved the efficacy of radiotherapy combined with anti-PD-1 immunotherapy, providing potential therapeutic strategies to overcome radioresistance.

Keywords:  Cancer; Immunology; Immunotherapy; Oncology; Radiation therapy

DOI:  https://doi.org/10.1172/JCI193945
J Immunother Cancer. 2025 Oct 05. pii: e012743. [Epub ahead of print]13(10):

Positive and negative roles of myeloid cells in cancer immunotherapy.

Jaroslav Zak, Judith A Varner.

  Myeloid cells are a diverse group of immune cell types with systemic and organ-specific functions. Myeloid cells are frequently found in the tumor microenvironment and their infiltration correlates with survival and response to treatment. High myeloid infiltration is typically a poor prognostic factor, and the immune suppressive and prometastatic roles of myeloid cells are well established. However, there is an increasing appreciation of the antitumor functions performed by myeloid cells, which include direct tumor cell killing, phagocytosis, antigen presentation and T and natural killer cell recruitment. Moreover, advances in immune phenotyping have uncovered myeloid subsets with positive prognostic significance, including subsets correlating with higher response rates to immunotherapy. This review summarizes recent progress in mapping and dissecting the opposing effects of myeloid cells on cancer progression and immunotherapy response. The overall impact of myeloid cells is context-dependent, and combination therapies are needed to leverage the antitumor potential of these cells.

Keywords:  Immunotherapy; Macrophage; Myeloid; Myeloid-derived suppressor cell - MDSC; Neutrophil

DOI:  https://doi.org/10.1136/jitc-2025-012743
Front Immunol. 2025 ;16 1627285

The role of dysbiosis in shaping host immunity in endometrial cancer development.

Wiktoria Wierzbińska, Olga Kuźmycz, Aleksandra Kowalczyk, Paweł Stączek.

  In recent years, research into the background of carcinogenic processes has increasingly focused on the role of the tumor microenvironment (TME) in tumorigenesis. In addition to the presence of tumor cells and non-malignant components, which include immune cells, extracellular matrix elements, stroma, and endothelial cells, the microbiome is now increasingly being classified as an integral part of the TME. The establishment of the Human Microbiome Project (HMP) in 2007 along with the development of next-generation sequencing (NGS) techniques proved to be a breakthrough in terms of human microbiota research, shedding new light on the existing knowledge of microorganisms inhabiting various niches of the human body and their functions. Emerging scientific evidence from preclinical and clinical studies indicates significant differences in the microbiome composition between tumor tissues and benign controls. The presence of specific pathogenic strains within a tissue may play a key role in the initiation and progression of inflammation, which not only may be directly responsible for the stimulation of tumorigenic processes but may also affect the destabilization of the host genome, causing significant disruption of its metabolism. The role of microorganisms in the induction and promotion of pathological processes, including cancer, has been confirmed in many studies to date. Recent years of research on the microbiota of the female reproductive tract (FRT) have not only indicated that the endometrium has its unique microbial composition but have also made it possible to point out differences in composition between the microbiome of healthy and tumor-lesioned tissue, suggesting a potential role for dysbiotic disorders in the pathogenesis of endometrial cancer (EC). In this review, we aim to highlight the complex interplay between bacterial interactions and host immunity, and how this phenomenon contributes to the development and progression of endometrial cancer.

Keywords:  dysbiosis; endometrial cancer; endometrial microbiota; estrabolome; gut microbiota; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1627285
J Transl Med. 2025 Oct 06. 23(1): 1055

Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.

Yinping Wang, Weijie Chen, Zida Wang, Siwen Cai, Xinnan Zhao, Jingsi Jin, Ting Gao, Junwen Qu.

   BACKGROUND: Immunometabolic adaptations may induce tumor immune escape and immunotherapeutic resistance, representing crucial mechanisms in cancer progression. Understanding the metabolic rewiring of tumor-infiltrating immune cells as tumors advance could enhance current immune-oncology treatments.
METHODS: In this study, we investigated metabolic heterogeneity in immune cells within both tumor and adjacent normal tissue using single-cell transcriptome profiling of colon cancer. We also utilized the MC38 colorectal cancer model, a commonly employed mouse tumor model, to assess the metabolic atlas of major immune cell populations in tumor and normal tissue.
RESULTS: We examined the immunometabolic features in tumor tissue and adjacent normal tissue using public single-cell transcriptomic datasets of colorectal cancer (CRC) patients, in which myeloid cells showed dominant metabolic activity. Using a mouse tumor model, we demonstrated distinct metabolic reprogramming of major immune cell types in tumor compared to normal tissue. Specifically, we observed increased glucose and lipid uptake, along with abundant lipid accumulation in tumor-infiltrating myeloid cells, particularly macrophages. Additionally, we identified diverse mitochondrial fitness and oxidative stress levels within the tumor immune microenvironment. Macrophages exhibited metabolic fitness, CD8+ T cells displayed mitochondrial depolarization, and neutrophils showed high oxidative stress. Furthermore, we investigated immunometabolic dynamics and observed augmented metabolic activity in immune cells infiltrating progressive and late stages of tumor development. Notably, intratumoral macrophages exhibited metabolic heterogeneity, characterized by robust lipid uptake and synthesis, which correlated with a pro-tumor phenotype and poor clinical outcomes.
CONCLUSION: Overall, our study unveils the heterogeneity and dynamics of metabolic properties in immune cells within the tumor microenvironment. These findings provide insights for developing therapeutic strategies that target metabolism to enhance antitumor immunity.

Keywords:  Colon cancer; Immune metabolism; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1186/s12967-025-07069-y
Cancer Immunol Res. 2025 Oct 08. OF1-OF2

CAR-ving a Path: Metalloprotease-Engineered CAR T Cells Tunnel through Solid Tumors.

Alessandro Gasparetto, Roberto Chiarle.

Overcoming the physical barriers of the tumor microenvironment remains a major obstacle for chimeric antigen receptor (CAR) T-cell therapy in solid tumors. In this issue, Van Pelt and colleagues show that engineering GD2-targeting CAR T cells to express matrix metalloproteinase 7 and osteopontin-b enhances their ability to infiltrate tumors rich in extracellular matrix. These modifications improve functionality in preclinical models without increasing off-target toxicity. The findings highlight a promising strategy to design CAR T cells with extracellular matrix-remodeling capabilities. See related article by Van Pelt et al., p. XX .

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1097
Front Biosci (Landmark Ed). 2025 Sep 23. 30(9): 37304

The Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions.

Bikesh K Nirala, Jason T Yustein.

  Cancer continues to be a significant global health issue, influenced by genetic mutations and external factors like carcinogenic exposure, lifestyle choices, and chronic inflammation. The myelocytomatosis (MYC) oncogene family, including c-MYC, MYCN, and MYCL, is essential in the development, progression, and metastasis of various cancers such as breast, colorectal, osteosarcoma, and neuroblastoma. Beyond its well-known roles in cell growth and metabolism, MYC significantly shapes the tumor immune microenvironment (TIME) by altering immune cell dynamics, antigen presentation, and checkpoint expression. It contributes to immune evasion by upregulating checkpoints such as programmed death-ligand 1 (PD-L1) and cluster of differentiation (CD)47, suppressing antigen-presenting major histocompatibility complex (MHC) molecules, and promoting the recruitment of suppressive immune cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). While direct targeting of MYC has proven challenging, recent advances in therapeutic strategies, including MYC-MYC-associated factor X (MAX) dimerization inhibitors, bromodomain and extra terminal domain (BET) and cyclin dependent kinase (CDK) inhibitors, synthetic lethality approaches, and epigenetic modulators, have shown promising results in preclinical and early clinical settings. This review discusses MYC's comprehensive impact on TIME and examines the promising therapeutic strategies of MYC inhibition in enhancing the effectiveness of immunotherapies, supported by recent preclinical and clinical findings.

Keywords:  MYC; cancer; immunotherapy; oncogene; tumor immune microenvironment

DOI:  https://doi.org/10.31083/FBL37304
ACS Biomater Sci Eng. 2025 Oct 07.

Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy.

Pankaj Yadav, Amit K Yadav, Dhiraj Bhatia.

  The tumor microenvironment (TME) is a critical orchestrator of cancer progression, shaped not only by genetic mutations but also by dynamic factors such as acidic pH, dysregulated extracellular matrix (ECM), immunosuppressive cells, and cytokine networks. These elements collectively foster therapeutic resistance and metastasis, challenging conventional treatments. Nanotechnology has emerged as a transformative approach to dismantling TME barriers, enabling precise targeting and enhanced drug delivery. In addition, a key focus is overcoming ECM density and immunosuppression. For instance, ECM-degrading nanoparticles (NPs) loaded with hyaluronidase or collagenase improve drug penetration, while immune-modulating NPs reprogram macrophages from protumor (M2) to antitumor (M1) phenotypes. Complementing these strategies, advances in immune cell engineering, such as chimeric antigen receptor (CAR) T cells or natural killer (NK) cells, are synergized with NPs-delivered checkpoint inhibitors to amplify antitumor immunity. Additionally, pH-sensitive and enzyme-responsive NPs exploit TME-specific conditions for controlled drug release, minimizing systemic toxicity. Despite promising preclinical results, clinical translation faces hurdles. Challenges include optimizing NPs' biocompatibility, scalability, and long-term safety as well as addressing interpatient TME heterogeneity. Thus, this review explores innovative NPs designs engineered to navigate the TME complexity, including surface modifications with antibodies, folic acid, transferrin, peptides, and amino acids. These functionalized NPs improve tumor-specific targeting while evading immune clearance, thereby enhancing chemotherapeutic efficacy and reducing off-target effects. Moreover, this review evaluates current progress in NPs-based clinical trials targeting the TME and discusses emerging theranostic platforms that combine real-time imaging with therapy. By integration of multidisciplinary insights from materials science, immunology, and systems biology, nanotechnology holds immense potential to unlock personalized cancer therapies. Future research must prioritize scalable manufacturing and robust biomarker-driven approaches to realize this paradigm shift in oncology fully.

Keywords:  cancer therapy; immune modulation; nanoparticles; surface modification; targeted drug delivery; tumor microenvironment

DOI:  https://doi.org/10.1021/acsbiomaterials.5c01120
Front Pharmacol. 2025 ;16 1673290

The physiological and pharmaceutical roles of MCTs and other ingredients in intravenous emulsions containing omega-3 enriched fish oil designed to mitigate cytokine release syndrome.

David F Driscoll, Bruce R Bistrian.

  Cytokine release syndrome (CRS) is a serious adverse effect often seen following the administration of cancer immunotherapy, particularly with chimeric antigen receptor (CAR) T cell therapy. Recently, we proposed the administration of precise amounts of the primary active ingredients found in fish oil (EPA + DHA) in combination with medium chain triglycerides (MCTs). Although there is a commercial injectable emulsion containing a refined-only fish oil, it is indicated as a nutritional supplement because it contains highly variable concentrations of the primary active ingredients (±50% of EPA + DHA). We suggested the application of a refined and enriched fish oil in order to provide the desired pharmacological doses according to the typical limits for drugs, i.e., EPA + DHA, within ±10% of the labeled amount. This tight tolerance is not achievable with "refined-only" fish oil indicated for nutrition support. The purpose of this review is to further describe the details of such a dosage form, with particular focus on other active ingredients in the proposed formulation. They play important roles in delivering a safe final product with multiple therapeutic targets for the acute systemic inflammatory response from CRS, as well as addressing chronic inflammation within the tumor microenvironment (TME).

Keywords:  CAR T cell therapy; cytokine release syndrome; long chain triglycerides; medium chain triglycerides; omega-3 fatty acids

DOI:  https://doi.org/10.3389/fphar.2025.1673290
Immunohorizons. 2025 Sep 17. pii: vlaf048. [Epub ahead of print]9(10):

Tumor cells upregulate CCL22 in a STING-dependent manner in response to paracrine factors released by STING-activated myeloid cells and type I interferons.

Elmira M Lomashvili, Jihyun Kim, Lingwei Kong, Pamela R Cook.

  Immunosuppressive elements within the tumor microenvironment include both regulatory T cells (Tregs) and M2 macrophages. A well-described mechanism of Treg recruitment occurs via the chemokine CCL22, and CCL22 has also recently been implicated in the polarization of tumor-associated macrophages to the M2a subtype. Our lab and others have shown that CCL22 is upregulated in cancer cells following activation of the stimulator of interferon genes (STING). STING triggers immune responses against pathogenic nucleic acids as well as self-DNA mislocalized to the cytoplasm, which can accumulate in cancer cells due to chromosomal instability, damaged mitochondria, and increased expression of LINE-1 retrotransposons. STING activation has been associated with both anti-tumor and pro-tumor immune responses, and a potential mechanism of STING-mediated immune evasion is through CCL22 upregulation. CCL22 was first characterized in macrophages, and here we investigate the effects of STING activation on CCL22 expression in macrophages and monocytes. We report that human macrophages and monocytes are resistant to CCL22 upregulation by STING, but that STING-activated macrophages and monocytes release unidentified paracrine factor(s) that dramatically increase CCL22 upregulation in cancer cells in a manner that remains STING-dependent, as evidenced by the inability of STING knockout cells to upregulate CCL22 in response to these factors. We further found that exogenous type I interferons, a major downstream product of STING activation, also upregulate CCL22 in cancer cells via a STING-dependent mechanism and that exogenous IFN-β can directly activate STING.

Keywords:  CCL22; IFN; STING; immunosuppression; macrophage

DOI:  https://doi.org/10.1093/immhor/vlaf048
Front Immunol. 2025 ;16 1675677

Microbial metabolites and their influence on the tumor microenvironment.

Huanglin Duan, Baisheng Xu, Peiyue Luo, Tao Chen, Jun Zou.

  While tumor immunotherapy has achieved remarkable progress in many hematological malignancies, its efficacy remains limited by key challenges, including the immunosuppressive microenvironment of solid tumors, metabolic abnormalities, and drug resistance. As a central mechanism underlying impaired immune function, metabolic reprogramming of immune cells has emerged as a pivotal focus for unraveling tumor immune evasion and therapeutic resistance. Advances in metagenomics have highlighted the significance of the human commensal microbiome as a 'second genome.' Microbial metabolites, whether circulating systemically or accumulating locally, serve as key messengers linking the microbiota to tumor immunometabolism. This review comprehensively examines the regulatory roles and metabolic mechanisms through which microbial metabolites-including short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and lipopolysaccharides (LPS)-modulate tumor immunity and immunotherapeutic responses via immune cell metabolism. These metabolites shape the tumor immune microenvironment and influence immunotherapeutic efficacy by reprogramming immune cell metabolic and biosynthetic pathways. This review underscores the central regulatory role of microbial metabolites as the 'second genome' in tumor immunometabolism, offering a theoretical foundation and potential targets to elucidate mechanisms of immunotherapeutic resistance and advance microbiota metabolism-based precision interventions.

Keywords:  immunometabolism; immunotherapy; microbial metabolites; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1675677
Biomater Sci. 2025 Oct 07.

Bacteria biohybrids integrating anticancer peptide-loaded nanoparticles for tumor immunotherapy through pyroptosis activation.

Shiyi Chen, Xunping Ouyang, Xue Wei, Gang He, Yiwen Xian, Chong Zhang, Decheng Wu.

Developing bacterial-based biohybrid systems that effectively integrate tumor-targeting, immune modulation, and advanced drug delivery remains a major challenge in cancer therapy. This is primarily due to the complexities of achieving selective tumor colonization, overcoming immune clearance mechanisms, and ensuring controlled drug release within the tumor microenvironment. Here, we introduce P/L@EcN, a bacteria biohybrid system that conjugates ROS-responsive, ruxotemitide (LTX-315)-loaded poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles (P/L-NPs) with the tumor-targeting probiotic Escherichia coli Nissle 1917 (EcN) via copper-free azide-alkyne click chemistry. This hybrid system exhibits enhanced tumor accumulation, improved cellular uptake, and deep tumor penetration, while effectively inducing pyroptosis through caspase-1-dependent pathways. In an in vivo orthotopic breast cancer model, P/L@EcN enhanced anti-tumor immunity by remodeling the tumor microenvironment, promoting the macrophage M1/M2 ratio, and reducing myeloid-derived suppressor cells (MDSCs), ultimately achieving significant tumor growth suppression without systemic toxicity. Together, these findings establish P/L@EcN as a promising biohybrid immunotherapy strategy that integrates bacterial-mediated targeting with immune activation, offering a powerful approach for cancer treatment.

DOI: https://doi.org/10.1039/d5bm00667h
MedComm (2020). 2025 Oct;6(10): e70413

Metabolite to Modifier: Lactate and Lactylation in the Evolution of Tumors.

Long Zhao, Haoyue Cui, Yutong Li, Yingjiang Ye, Zhanlong Shen.

  Lactate, once dismissed as a mere by-product of cancer metabolism, has emerged as a pivotal factor in tumor progression, exerting diverse effects on metabolic reprogramming and immune modulation. Lactate enhances tumor cell adaptability through sustained glycolysis and concurrently shapes the tumor microenvironment by modulating immune, stromal, and endothelial cell function. This review highlights the evolving understanding of lactate's role, extending beyond the Warburg effect to its regulatory capacity via lactylation, a recently identified post-translational modification. The complex interaction between lactate and tumor biology is examined, emphasizing its influence on the tumor microenvironment and immune dynamics. Additionally, potential therapeutic strategies targeting lactate metabolism and transport are explored, along with lactylation regulation by histone-modifying enzymes. Inhibitors targeting lactate production and transport, especially those against lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), have shown considerable potential in preclinical and early clinical studies. Recent advancements are discussed, underscoring the potential of integrating metabolic regulation with immunotherapies, thereby offering a dual pathway in cancer treatment. These insights establish lactate and lactylation as pivotal modulators of tumor biology and highlight their potential as targets in precision oncology.

Keywords:  cancer therapy; immune modulation; lactate; lactylation; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70413
Front Immunol. 2025 ;16 1667464

Decoding immune low-response states in ovarian cancer: insights from single-cell and spatial transcriptomics for precision immunotherapy.

Yalan Yan, Jiaan Lu, Huanyu Luo, Zizhang Wang, Ke Xu, Lexin Wang, Qin Wang.

  Ovarian cancer represents a typically immune "cold" tumor, where obvious immunosuppression, spatial T-cell exclusion, and cellular dysfunction collectively limit immunotherapy effectiveness. Especially in high-grade serous ovarian carcinoma (HGSOC), the immune low-response state is driven by complex interactions among tumor-associated macrophages (TAMs), suppressive stromal networks, and the T-cell compartment (regulatory T cells, Tregs, and exhausted effector T cells). Emerging multi-omics technologies-particularly single-cell RNA sequencing and spatial transcriptomics-have showed the heterogeneity and spatial immune organization underlying this suppressed state. Here, we integrate these datasets to describe TAM phenotypes and spatial niches, T-cell exhaustion, Tregs accumulation, NK-cell dysfunction, and stromal barriers that enforce exclusion. We then derive phenotype-guided combination strategies to remodel the tumor microenvironment and improve responsiveness to immune checkpoint blockade. This synthesis provides a concise, multi-dimensional framework for precision immunotherapy and for overcoming resistance in immune-low ovarian cancers.

Keywords:  T-cell exhaustion; immune low-response state; immunotherapy resistance; ovarian cancer; single-cell RNA sequencing; spatial transcriptomics; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1667464
ACS Nano. 2025 Oct 10.

Spatiotemporally Controlled Nanomicelles for Synergistic Phototherapy and Immune Reprogramming in Triple-Negative Breast Cancer.

Di Chang, Jie Yang, Yingbo Li, Shudan Min, Yuanyuan Ma, Tingting Xu, Zhiqi Zhang, Xiuquan Zhu, Xiaoxuan Xu, Chunqiang Lu, Ben Zhao, Min Chen, Zebin Xiao, Jinbing Xie, Shenghong Ju.

  Immune reprogramming of the tumor microenvironment (TME) represents a promising strategy to overcome immunosuppressive barriers in triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are key contributors to immune evasion and tumor progression; however, existing strategies are limited by TAM heterogeneity, poor tumor-specific delivery, and transient immune activation. Here, we developed a self-assembled, reactive oxygen species (ROS)-responsive nanomicelle (IR825@HRG) for codelivery of the near-infrared photosensitizer IR825 and the immunomodulatory protein histidine-rich glycoprotein (HRG), which is capable of reprogramming TAMs. Upon laser irradiation, IR825 triggers ROS generation and localized hyperthermia, synergistically eradicating tumor cells via photothermal and photodynamic effects. Simultaneously, ROS cleave thioketal linkers to release HRG in a spatiotemporally controlled manner, achieving a 2.3-fold higher tumor accumulation than free HRG and effectively reprogramming TAMs from M2- to M1-like phenotypes. Moreover, ROS-mediated immunogenic cell death further enhances systemic antitumor immunity, suppressing both primary tumors and metastases. By transforming the TME from "cold" to "hot", laser-activated IR825@HRG nanomicelles achieved combinatorial photoimmunotherapy in TNBC. Together, this facile, highly responsive, and multifunctional nanoplatform offers a robust strategy to integrate phototherapy with immunotherapy to reprogram the TME in poorly immunogenic tumors.

Keywords:  controllable release; nanomicelles; photoimmunotherapy; synergistic therapy; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.5c09413
Life Metab. 2025 Dec;4(6): loaf032

Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.

Thomas Pfefer, Luke A J O'Neill.

Clark et al. showcase that interferons (IFNs) trigger a functional reprogramming of tumor-associated macrophages (TAMs) by downregulating NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4), a key subunit of mitochondrial complex Ⅳ. This drives a transition from protumor TAMs to antitumor IFN-associated TAMs (IFN-TAMs) through activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This mechanism can be leveraged to boost antitumor immunity and improve responses to immune checkpoint blockade.

DOI: https://doi.org/10.1093/lifemeta/loaf032
Cell Death Discov. 2025 Oct 06. 11(1): 434

Exosomal non-coding RNAs: mediators of crosstalk between cancer and cancer stem cells.

Shuangmin Wang, Jiaojiao Shu, Nuoxin Wang, Zhixu He.

Current advances in oncology have recognized two distinct cell subpopulations in tumors that include (1) a rare subpopulation, cancer stem cells (CSCs), which is considered to be the "seed" of the tumor, with therapy-resistant properties and as key drivers of tumor aggressiveness, and (2) the remaining bulk one, non-CSCs, all differentiated from the CSCs. Within the tumor microenvironment (TME), exosomes secreted by either CSCs or non-CSCs, containing multiple biomolecular cargos, mediate communication between both of the tumor cell subpopulations and play a vital role in promoting tumor progression. Specifically, a class of biomolecular cargo, non-coding RNAs (ncRNAs) that do not code for proteins during translation, has recently been highlighted to be a key participant in oncobiological processes. To comprehensively illuminate the mechanism of exosomal ncRNAs in mediating bidirectional communication between CSCs and differentiated tumor cells within the TME, we systematically analyzed the state-of-the-art literature from PubMed on this topic. It is revealed that: (1) Non-CSC exosomal ncRNAs enhance CSC stemness via upregulating stemness marker expression and activating stemness-reinforcing signaling pathways; (2) CSC-derived exosomal ncRNAs reciprocally mediate tumor progression by enhancing stemness, metastasis, angiogenesis, chemoresistance, and immune suppression of non-CSCs; (3) These tumor-derived exosomal ncRNAs possess the potentials as liquid biopsy biomarkers for early metastasis detection, and treatment targets or drug delivery systems for precision cancer therapy. It is therefore concluded that exosomal ncRNAs serve as critical communication bridges within TME, creating a self-reinforcing tumor-promoting loop, and therapeutically targeting exosomal ncRNAs could disrupt the crosstalk between CSCs and non-CSCs to delay the tumor progression. These findings provide a framework for developing combinatorial strategies against therapy-resistant malignancies.

DOI: https://doi.org/10.1038/s41420-025-02726-z
Biochem Biophys Res Commun. 2025 Sep 26. pii: S0006-291X(25)01427-5. [Epub ahead of print]786 152711

Immune-modulatory effects of low-dose radiotherapy through macrophage polarization and transcriptional rewiring in triple-negative breast cancer.

Hui Li, Jeanny Kwon, Hak Jae Kim, Byoung Hyuck Kim.

   BACKGROUND: Despite recent advancements with immune checkpoint inhibitors, a significant proportion of patients, particularly those with triple-negative breast cancer, exhibit resistance to these therapies. To address this challenge, we investigated whether adding low-dose-per-fraction radiotherapy (LDRT) could remodel the tumor microenvironment (TME) and enhance the efficacy of PD-1 blockade.
METHODS: Luciferase-expressing 4T1 breast-cancer cells were inoculated subcutaneously at multiple sites in 6-week-old BALB/c mice. The mice were divided into seven groups: (i) untreated control; (ii) anti-PD-1 antibody alone (0 Gy); and (iii) anti-PD-1 combined with single-fraction LDRT of 0.5, 1.0, 1.5, 2.0 or 5.0 Gy. Radiation was delivered to one tumor focus, followed by intraperitoneal injection of anti-mPD-1. Directly irradiated tumors (RT tumor) and non-irradiated tumors (NT tumor), and spleen samples were collected for mRNA sequencing and flow cytometry analysis.
RESULTS: LDRT could suppress tumor progression under PD-1 inhibition dependent manner, with 1.0-1.5 Gy providing considerable tumor growth delay in RT tumors. Flow cytometry revealed a non-linear relationship between radiation dose and TME modulation, where intermediate doses shifted macrophages towards an M1-like phenotype, whereas higher doses restored an M2-like state. Transcriptomic clustering revealed three gene-expression trajectories: monotonically increasing with dose, peaking at 1.5 Gy, or decreasing with dose. Genes maximally induced at 1.5 Gy were enriched for cytoplasmic translation, hypoxia response and myeloid differentiation. In spleen tissue, a 1.0 Gy-specific signature implicated chromosome-segregation and ubiquitin-ligase pathways. Pathway analysis further demonstrated significant alterations in WNT, VEGF, and androgen signaling, particularly at 1.5 Gy CONCLUSION: LDRT, particularly at intermediate dose ranges, delays tumor growth and reprogram the TME to favor PD-1 inhibition in a cold tumor model. These effects are underpinned by transcriptional changes in key biological processes, suggesting that pretreatment with LDRT represents a promising strategy to enhance the efficacy of immune checkpoint inhibitors.

Keywords:  Breast cancer; Low-dose radiation therapy; PD-1 inhibitor; Tumor microenvironment (TME); Tumor-associated macrophage (TAM)

DOI:  https://doi.org/10.1016/j.bbrc.2025.152711