bims-flamet 2025-03-16 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–03–16
29 papers selected by
Peio Azcoaga, Biodonostia HRI

Targeting cGAS-STING pathway for reprogramming tumor-associated macrophages to enhance anti-tumor immunotherapy.
Protease regulation of tumor-immune cell symbiosis.
Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling.
Regulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment?
Tumor Microenvironment On-A-Chip and Single-Cell Analysis Reveal Synergistic Stromal-Immune Crosstalk on Breast Cancer Progression.
eNAMPT/Ac-STAT3/DIRAS2 Axis Promotes Development and Cancer Stemness in Triple-Negative Breast Cancer by Enhancing Cytokine Crosstalk Between Tumor-Associated Macrophages and Cancer Cells.
Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities.
Thyroid Cancer-The Tumor Immune Microenvironment (TIME) over Time and Space.
Tumor-infiltrating and circulating B cells mediate local and systemic immunomodulatory mechanisms in Glioblastoma.
KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy.
Osteopontin promotes tumor microenvironment remodeling and therapy resistance.
The hidden messengers: Tumor microenvironment-derived exosomal ceRNAs in gastric cancer progression.
Unveiling the Role of the Cellular Tumor Microenvironment and the Therapeutic Targets it Provides in Cutaneous T-Cell Lymphoma.
Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products.
Current advancement of immune function paradox of tumour-infiltrating cells and their immunotherapeutic targets: a mini-review.
PKN2 enhances the immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells in esophageal carcinoma by mediating fatty acid oxidation.
Immunotherapy in cervical cancer: an innovative approach for better treatment outcomes.
Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.
Editorial: Role of fibroblast in cancer.
RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
Nanobody-enhanced chimeric antigen receptor T-cell therapy: overcoming barriers in solid tumors with VHH and VNAR-based constructs.
Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.
Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets.
Ex.50.T aptamer impairs tumor-stroma cross-talk in breast cancer by targeting gremlin-1.
Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications.
Analyze the Diversity and Function of Immune Cells in the Tumor Microenvironment From the Perspective of Single-Cell RNA Sequencing.
Divergent impact of endotoxin priming and endotoxin tolerance on macrophage responses to cancer cells.
Integrating spatial and single-cell transcriptomes reveals the role of COL1A2(+) MMP1(+/-) cancer-associated fibroblasts in ER-positive breast cancer.
The role of tumor-associated macrophages in lung cancer.

Biomark Res. 2025 Mar 12. 13(1): 43

Targeting cGAS-STING pathway for reprogramming tumor-associated macrophages to enhance anti-tumor immunotherapy.

Weiyue Zhang, Xin Huang.

  The cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) signaling pathway plays a crucial role in activating innate and specific immunity in anti-tumor immunotherapy. As the major infiltrating cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) could be polarized into either anti-tumor M1 or pro-tumor M2 types based on various stimuli. Accordingly, targeted reprogramming TAMs to restore immune balance shows promise as an effective anti-tumor strategy. In this review, we aim to target cGAS-STING pathway for reprogramming TAMs to enhance anti-tumor immunotherapy. We investigated the double-edged sword effects of cGAS-STING in regulating TME. The regulative roles of cGAS-STING pathway in TAMs and its impact on the TME were further revealed. More importantly, several strategies of targeting cGAS-STING for reprogramming TAMs were designed for enhancing anti-tumor immunotherapy. Taken together, targeting cGAS-STING pathway for reprogramming TAMs in TME might be a promising strategy to enhance anti-tumor immunotherapy.

Keywords:  Immunotherapy; Tumor; Tumor microenvironment; Tumor-associated macrophages; cGAS-STING

DOI:  https://doi.org/10.1186/s40364-025-00750-w
Trends Cancer. 2025 Mar 07. pii: S2405-8033(25)00052-4. [Epub ahead of print]

Protease regulation of tumor-immune cell symbiosis.

Lizhi Pang, Yuyun Huang, Jean Huang-Gao, Peiwen Chen.

  Proteases play a crucial role in cancer progression and are traditionally known for their protumorigenic role by degrading the extracellular matrix (ECM). Emerging evidence indicates that proteases, such as caspases, cathepsins, and ubiquitin-specific proteases (USPs), regulate diverse immunomodulatory substrates or signals in the tumor microenvironment (TME), generating symbiotic interactions between cancer cells and immune cells. These interactions are critical for tumor progression and immunotherapy resistance across cancer types. In this review, we highlight recent insights into protease-mediated tumor-immune cell crosstalk, emphasizing how this symbiosis affects tumor progression and immunosuppression. Moreover, we discuss therapeutic strategies that exploit protease-mediated tumor-immune cell interactions to inhibit tumor progression and sensitize immunologically 'cold' tumors to immunotherapies, especially immune checkpoint inhibitor (ICI) therapy.

Keywords:  immune checkpoint inhibitor; immunotherapy; protease; tumor microenvironment; tumor–immune cell crosstalk

DOI:  https://doi.org/10.1016/j.trecan.2025.02.004
Immune Netw. 2025 Feb;25(1): e8

Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling.

Tzu-Hsuan Chang, Ping-Chih Ho.

  IFNs play a critical role in cancer biology, including impacting tumor cell behavior and instructing the tumor microenvironment (TME). IFNs recently have been shown to reprogram tumor metabolism through distinct mechanisms. Furthermore, IFNs shape the TME by modulating immune cell infiltration and function, contributing to the intricate interaction between the tumor and stromal cells. This review summarizes the effects of IFNs on metabolic reprogramming and their impacts on the function of immune cells within the TME, with a particular focus on the dual roles of IFNs in mediating both anti-tumor and pro-tumor immune responses. Understanding the significance of IFNs-mediated processes aids to advise future therapeutic strategies in cancer treatment.

Keywords:  Antitumor; Interferon; Metabolism; Tumor microenvironment

DOI:  https://doi.org/10.4110/in.2025.25.e8
Immune Netw. 2025 Feb;25(1): e13

Regulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment?

Jihyoun Kim, Jiaoran Li, Jun Wei, Seon Ah Lim.

  Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.

Keywords:  Immune evasion; Immunometabolism; Immunotherapy; Regulatory T cell; Tumor microenvironment

DOI:  https://doi.org/10.4110/in.2025.25.e13
Adv Sci (Weinh). 2025 Mar 08. e2413457

Tumor Microenvironment On-A-Chip and Single-Cell Analysis Reveal Synergistic Stromal-Immune Crosstalk on Breast Cancer Progression.

Kalpana Ravi, Yining Zhang, Lydia Sakala, Twinkle Jina Minette Manoharan, Barbara Pockaj, Joshua LaBaer, Jin G Park, Mehdi Nikkhah.

  Solid tumors develop within a complex environment called the tumor microenvironment (TME), which is sculpted by the presence of other cells, such as cancer-associated fibroblasts (CAFs) and immune cells like macrophages (Mφs). Despite the presence of immune cells, tumor cells orchestrate a tumor-supportive environment through intricate interaction with the components of the TME. However, the specific mechanism by which this intercellular dialogue is regulated is not fully understood. To that end, the development of an organotypic 3D breast TME-on-a-chip (TMEC) model, integrated with single-cell RNA sequencing analysis, is reported to mechanistically evaluate the progression of triple-negative breast cancer (TNBC) cells in the presence of patient-derived CAFs and Mφs. Extensive functional assays, including invasion and morphometric characterization, reveal the synergistic influence of CAFs and Mφs on tumor cells. Furthermore, gene expression and pathway enrichment analyses identify the involvement of the KYNU gene, suggesting a potential immune evasion mechanism through the kynurenine pathway. Lastly, the pharmacological targeting of the identified pathway is investigated.

Keywords:  cancer‐associated fibroblast (CAFs); macrophages; microfluidics; migration; scRNA sequencing; triple‐negative breast cancer (TNBC); tumor microenvironment (TME)

DOI:  https://doi.org/10.1002/advs.202413457
Int J Biol Sci. 2025 ;21(5): 2027-2047

eNAMPT/Ac-STAT3/DIRAS2 Axis Promotes Development and Cancer Stemness in Triple-Negative Breast Cancer by Enhancing Cytokine Crosstalk Between Tumor-Associated Macrophages and Cancer Cells.

Lifen Zhang, Lu Wang, Ziyao Xu, Xingmei Zhang, Shaoyu Guan, Zhe Liu, Shanzhi Gu, Lin Zhao, Weichao Bai, Tian Li, Xinhan Zhao.

  The intricate relationship between tumor-associated macrophages (TAMs) and cancer cells is pivotal for carcinogenesis, with TAMs being integral to the tumor microenvironment (TME). This study explores the novel mechanisms by which TAMs regulate the progression of triple-negative breast cancer (TNBC) within the TME. Using a co-culture system and methodologies such as cytokine arrays, proteomics, and CRISPR-Cas9, we investigated the crosstalk between TAMs and TNBC cells. We found that high levels of CD163+ TAMs in TNBC tissues correlate with poor prognosis. TNBC cell-conditioned medium induces macrophage polarization towards the M2 phenotype, enhancing TNBC cell migration, invasion, and stemness through the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT binding to CCR5 on TNBC cells activates STAT3, leading to the downregulation of the tumor suppressor DIRAS2 and an increase in CCL2, which promotes a macrophage recruitment loop. Intervention at the eNAMPT/CCR5 or CCL2 level disrupts this loop, mitigating TAM-induced effects. Our findings uncover a cytokine communication mechanism between immune and cancer cells, suggesting potential targets for TNBC detection and treatment.

Keywords:  Cancer stemness; Extracellular nicotinamide phosphoribosyltransferase; Metastasis; Triple-negative breast cancer; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.103723
J Transl Med. 2025 Mar 12. 23(1): 315

Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities.

Jiachun Sun, Yi Chen, Ziyi Xu, Weizheng Wang, Penghui Li.

  Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.

Keywords:  CRC; GSIs; Immune; Notch signaling; Prognosis

DOI:  https://doi.org/10.1186/s12967-025-06282-z
Cancers (Basel). 2025 Feb 26. pii: 794. [Epub ahead of print]17(5):

Thyroid Cancer-The Tumor Immune Microenvironment (TIME) over Time and Space.

Juan Carlos Jaume.

  In thyroid cancer, the tumor immune microenvironment (TIME) plays a crucial role in cancer development, progression and response to treatment. Like many other cancers, thyroid cancer creates a complex network of interactions with immune cells directly (cell-to-cell) and via humoral mediators (i.e., cytokines). This dynamic microenvironment undergoes constant modification, which can lead to changes in the immunophenotype that might explain cancer progression, dedifferentiation and resistance to treatment. According to the cancer immunoediting hypothesis, cancerous tumors can shape their immune microenvironment to create an immunosuppressive milieu that allows them to evade classic immune surveillance. One mechanism by which this occurs is through the reprogramming of immune cells, often shifting their phenotypes from cytotoxic to regulatory. Recent research has shed light on cellular components and molecular interactions within the thyroid cancer TIME. Immune cells such as Tumor-Associated Lymphocytes (TALs), myeloid-derived suppressor cells (MDSCs), Tumor-Associated Macrophages (TAMs) and Double-Negative (DN) T cells seem to play key roles in shaping the immune response to thyroid cancer. Additionally, cytokines, chemokines and other signaling molecules contribute to the communication and regulation of immune cells within that microenvironment. By studying these interactions, researchers aim to uncover not just potential therapeutic targets but also biomarkers of thyroid cancer that could provide clues on severity and progression. Based on that knowledge, strategies such as the use of immune checkpoint inhibitors, antigen-specific targeted immunotherapies, and immunomodulatory agents are being explored to enhance the anti-tumor immune response and overcome cancer immunosuppressive mechanisms. In this review, we analyze the available literature and provide our own experience to unravel the complexity of the thyroid immune microenvironment. Continued research in this area holds promise for improving outcomes through the identification of immune markers of severity/progression of thyroid cancer and the development of innovative immunotherapeutic approaches.

Keywords:  doble negative T cells (DN T cells); myeloid-derived suppressor cells (MDSCs); thyroid cancer; tumor immune microenvironment (TIME); tumor-associated lymphocytes (TALs); tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers17050794
J Neurooncol. 2025 Mar 13.

Tumor-infiltrating and circulating B cells mediate local and systemic immunomodulatory mechanisms in Glioblastoma.

Pierfrancesco De Domenico, Filippo Gagliardi, Francesca Roncelli, Silvia Snider, Pietro Mortini.

   BACKGROUND: Glioblastoma (GBM) demonstrates extensive immunomodulatory mechanisms that challenge effective therapeutic interventions. These phenomena extend well beyond the tumor microenvironment (TME) and are reflected in the circulating immunophenotype. B lymphocytes (B cells) have received limited attention in GBM studies despite their emerging importance in mediating both local and systemic immune responses. Recent findings highlight the complex regulatory interactions between B cells and other immune cell populations, including tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and other infiltrating lymphocytes (TILs). B cells are believed to hinder the efficacy of modern immunotherapy strategies focusing on T cells.
METHODS: This is a focused review of available evidence regarding B cells in GBM through January 2025.
RESULTS: Peripheral blood reflects a systemically dampened immune response, with sustained lymphopenia, increased plasma cells, and dysfunctional memory B cells. The tumor immune landscape is enriched in cells of B-lineage. Subsets of poorly characterized B regulatory cells (Bregs) populate the TME, developing their phenotype due to their proximity to MDSCs, TAMs, and tumoral cells. The Bregs inhibit CD8+ T activity and may have potential prognostic significance.
CONCLUSION: Understanding the role of B cells, how they are recruited, and their differentiation shifted towards an immunomodulatory role could inform better therapeutic strategies and unleash their full antitumoral potential in GBM.

Keywords:  B cells; B lymphocytes; B regulatory cells; Bregs; Glioblastoma

DOI:  https://doi.org/10.1007/s11060-025-04989-z
Cancers (Basel). 2025 Feb 25. pii: 785. [Epub ahead of print]17(5):

KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy.

Priyanka Uniyal, Vivek Kumar Kashyap, Tapan Behl, Deepak Parashar, Ravi Rawat.

  The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.

Keywords:  KRAS mutation; cancer; immunotherapy; oncogene; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17050785
Cancer Lett. 2025 Mar 08. pii: S0304-3835(25)00182-X. [Epub ahead of print]617 217618

Osteopontin promotes tumor microenvironment remodeling and therapy resistance.

Chao Liu, Shunjin Xia, Bo Wang, Jiayong Li, Xuyan Wang, Yu Ren, Xuan Zhou.

Osteopontin (OPN) is a multifunctional secretory protein which can be expressed and secreted by a variety of tumor cells and immune cells. Tumor microenvironment remodeling provides favorable conditions for tumor progression, immune escape and therapy resistance. As a bridge molecule in crosstalk between tumor cells and tumor microenvironment, OPN can not only come from tumor cells to regulate the functions of various immune cells, promoting the formation of immunosuppressive environment, but also can be secreted by immune cells to act on tumor cells, leading to tumor progression, thus constructing a positive feedback regulatory network. Here, we summarize the molecular structure, source and receptor of OPN, and clarify the mechanism of OPN on tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, tumor progression and therapy resistance to comprehensively understand the great potential of OPN as a tumor biomarker and therapeutic target.

DOI: https://doi.org/10.1016/j.canlet.2025.217618
Pathol Res Pract. 2025 Mar 08. pii: S0344-0338(25)00097-4. [Epub ahead of print]269 155905

The hidden messengers: Tumor microenvironment-derived exosomal ceRNAs in gastric cancer progression.

Mohamed J Saadh, Hanan Hassan Ahmed, Radhwan Abdul Kareem, Ashok Kumar Bishoyi, R Roopashree, Debasish Shit, Renu Arya, Kamal Kant Joshi, Hayder Naji Sameer, Ahmed Yaseen, Zainab H Athab, Mohaned Adil.

  The tumor microenvironment (TME) plays a crucial role in the development and progression of gastric cancer (GC). The TME comprises a network of cancer cells, immune cells, fibroblasts, endothelial cells, and extracellular matrix components, which provide a supportive niche for cancer cells. This study investigates the role of TME-derived exosomal competitive endogenous RNAs (ceRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as major regulating agents in GC development. Exosomal ceRNAs control gene expression across several TME components, amplifying cancer hallmarks like cell proliferation, invasion, metastases, and chemoresistance. They promote dynamic interplay between cancer cells and adjacent stromal cells, enabling tumor development through immune suppression, angiogenesis, and epithelial-mesenchymal transition (EMT). Exosomal ceRNAs can modify the TME, creating a pro-tumorigenic milieu and preparing cancer cells to avoid immunological responses, defy death, and adapt to therapeutic pressures. This review highlights the understudied interactions between the TME and exosomal ceRNAs in gastric cancer and emphasizes their potential utility as diagnostic and therapeutic tools.

Keywords:  Chemoresistance; Competing endogenous RNAs; Exosomes; Gastric cancer; Immune evasion; Tumor microenvironment; ceRNAs; circRNAs; lncRNAs

DOI:  https://doi.org/10.1016/j.prp.2025.155905
Curr Oncol Rep. 2025 Mar 08.

Unveiling the Role of the Cellular Tumor Microenvironment and the Therapeutic Targets it Provides in Cutaneous T-Cell Lymphoma.

Nikolaos A Chinas, Stella Kaliampou, Vasiliki Nikolaou.

   PURPOSE OF REVIEW: Cutaneous T-Cell Lymphoma (CTCL) poses challenges both in diagnosis and prognosis. The purpose of this review is to address the role of profiling immune and non-immune cells in the tumor microenvironment (TME) as it provides information for better diagnosis, prognosis, biomarker discovery, and personalized treatment strategies.
RECENT FINDINGS: Recent evidence suggests that the progression of CTCL is closely linked to the Tumor Microenvironment (TME) which comprises various cell types including immune cells, stromal cells, blood vessels, and the extracellular matrix. Cell profiling within the TME demonstrates the perplexity of intracellular communication of the different cell fates and their mediators as the disease progresses. CTCL as a rare form of non-Hodgkin lymphoma often misdiagnosed due to its similarity to other skin conditions. It encompasses diseases like Mycosis fungoides (MF) and Sézary Syndrome (SS), with the latter being more severe. Advances in studying the TME have shown its pivotal role in CTCL progression, highlighting the need for comprehensive cell profiling to enhance diagnosis, prognosis, and treatment personalization.

Keywords:  CTCL; Cells; Mycosis Fungoides; Sézary Syndrome; Therapeutic Targets; Tumor Microenvironment

DOI:  https://doi.org/10.1007/s11912-025-01646-6
Front Immunol. 2025 ;16 1552010

Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products.

Dongyang Li, Xintian Lan, Linyi Xu, Shuo Zhou, Haoming Luo, Xiaoying Zhang, Wenbo Yu, Yonggang Yang, Xiaoxue Fang.

  In recent years, tumor immunotherapy has made significant breakthroughs in the treatment of malignant tumors. However, individual differences in efficacy have been observed in clinical practice. There is increasing evidence that gut microbial metabolites influence the efficacy of distal tumor immunotherapy via the gut-liver axis, the gut-brain axis and the gut-breast axis, a process that may involve modulating the expression of immune cells and cytokines in the tumor microenvironment (TME). In this review, we systematically explore the relationship between gut microbial metabolites and tumor immunotherapy, and examine the corresponding natural products and their mechanisms of action. The in-depth exploration of this research area will provide new ideas and strategies to enhance the efficacy of tumor immunotherapy and mitigate adverse effects.

Keywords:  gut microbial metabolites; immune; mechanism; natural products; tumor

DOI:  https://doi.org/10.3389/fimmu.2025.1552010
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 10.

Current advancement of immune function paradox of tumour-infiltrating cells and their immunotherapeutic targets: a mini-review.

Veena V Tom, Ann Mary Jose, Sumit Mallick, Athira Sasidharan, Rakshita Pawar, Yogish Somayaji, Ronald Fernandes.

  Cancer immunotherapy has long been an essential segment of current research and presents several problems to contemporary medicine. Though their precise roles are still elusive, recent studies have highlighted the importance of both innate and adaptive immune defence systems in the development and management of cancer. The immune system plays a crucial role in cancer prevention and control by identifying and eliminating abnormal cells. This activity can be evidenced in tumour-infiltrating lymphocytes (TILs), immune cells found within and surrounding tumours. TILs often correlate with better patient outcomes, indicating an active immune response against the cancer. This review investigates how these immune systems help tumour cells acquire the ability to infiltrate malignantly and elude immune defences. Tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are among the invading immune cell types whose roles in tumour development and immune suppression are investigated. These cells help cancers avoid being detected by the immune system, which increases their aggressiveness and ability to spread. Further, we have discussed the potential treatment approaches that target these immune processes, including immune checkpoint inhibitors (ICIs) and cutting-edge immunotherapies intended to reestablish robust anti-tumour responses. Researchers can find new ways to improve the efficacy of cancer immunotherapies by comprehending the intricate relationships between malignancies and the immune system. Moreover, we have summarized how targeting the immune response leads to more potent medications, enhancing the patient's outcome and survival.

Keywords:  Cancer immunology; Immune evasion; Immunotherapy; Tumour microenvironment; Tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00210-025-03985-4
Mol Med. 2025 Mar 11. 31(1): 92

PKN2 enhances the immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells in esophageal carcinoma by mediating fatty acid oxidation.

Xiao Fu, GuoQing Zhang, ZhiChao Hou, TingTing Fu, GuangHui Cui.

   BACKGROUND: Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment reduce the efficacy of immunotherapy. PKN2 plays a role in colon cancer, but its function in esophageal cancer (EC) remains unclear. This study investigated PKN2 expression in MDSCs derived from EC tissues and determined whether PKN2 regulates immunosuppressive activity of MDSCs by mediating fatty acid oxidation (FAO).
MATERIALS AND METHODS: PKN2 expression was determined in GEO database, EC patients, and 4-NQO-induced EC mice, as well as in different types of immune cells. The effect of PKN2 on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was investigated by co-culture of PMN-MDSCs and CD4+/CD8+ T cells. The co-culture of patient-derived organoids and autologous immune cells was performed to observe the effect of PKN2 on the immunosuppressive function of PMN-MDSCs.
RESULTS: PKN2 is highly expressed in EC tumor tissues compared to normal tissues, especially in tumor-infiltrated PMN-MDSCs. Overexpressing PKN2 in PMN-MDSCs contributes to the immunosuppressive activity of PMN-MDSCs in vitro. PKN2-overexpressing PMN-MDSCs inhibited the killing ability of cytotoxic T lymphocytes and promoted EC organoid growth. PKN2 promotes FAO in PMN-MDSCs via CPT1B (a key enzyme of FAO). Mechanistically, PKN2 promotes CPT1B transcription by upregulating STAT3 phosphorylation.
CONCLUSIONS: PKN2 expression was increased in PMN-MDSCs derived from human and mouse EC tissues. PKN2 plays a role in enhancing the immunosuppressive activity of PMN-MDSCs by facilitating STAT3 phosphorylation and CPT1B transcription, which in turn leads to increased CPT1B-mediated FAO in PMN-MDSCs. Targeted inhibition of PKN2 is expected to improve immunotherapeutic efficacy in EC patients.

Keywords:  Fatty acid oxidation; Immunosuppressive activity; Myeloid-derived suppressor cells; Organoid; PKN2

DOI:  https://doi.org/10.1186/s10020-025-01132-6
Explor Target Antitumor Ther. 2025 ;6 1002296

Immunotherapy in cervical cancer: an innovative approach for better treatment outcomes.

Treshita Dey, Sushma Agrawal.

  Cervical cancer remains a significant global health challenge, ranking as the fourth most common cancer among women. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiological factor, leading to immune evasion mechanisms that promote tumor development and progression. Immunotherapy has emerged as a transformative approach in the management of cervical cancer, aiming to restore and enhance the body's immune response against tumor cells. Checkpoint inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1) have shown promising results in patients with advanced or recurrent cervical cancer. Pembrolizumab, a PD-1 inhibitor, has been approved for PD-L1-positive cervical cancer, demonstrating durable responses. However, low response rates necessitate exploration of combination strategies. Trials are underway combining checkpoint inhibitors with chemotherapy, radiation, or other immunotherapeutic agents to enhance efficacy. Therapeutic vaccines targeting HPV antigens, such as E6 and E7 oncoproteins, are also a focus of active research. These vaccines aim to elicit robust cytotoxic T-cell responses, offering a potential strategy for early intervention and disease control. Adoptive T-cell therapies, including engineered T-cell receptor (TCR) and chimeric antigen receptor (CAR)-T cells, represent cutting-edge advancements, though challenges with tumor heterogeneity and off-target effects persist. However, challenges such as limited response rates and immune evasion mechanisms remain. The tumor microenvironment (TME) in cervical cancer, characterized by immunosuppressive cells and cytokines, poses a significant barrier to effective immunotherapy. Emerging approaches targeting the TME, such as cytokine modulation, hold promise in overcoming resistance mechanisms. Key gaps include a lack of biomarkers for patient selection, insufficient understanding of TME dynamics, and suboptimal strategies for overcoming antigen heterogeneity and immune resistance. This review addresses these issues by providing a comprehensive analysis of the current landscape of cervical cancer immunotherapy, identifying critical barriers, and highlighting emerging approaches, such as combination therapies, novel immune targets, and strategies to modulate the TME, to guide future research and clinical practice.

Keywords:  Immunotherapy; cervical cancer; immune-check point inhibitors; metastatic cervical cancer; radio-immunotherapy

DOI:  https://doi.org/10.37349/etat.2025.1002296
Int J Mol Sci. 2025 Feb 22. pii: 1879. [Epub ahead of print]26(5):

Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.

Wiktoria Andryszkiewicz, Julia Gąsiorowska, Maja Kübler, Karolina Kublińska, Agata Pałkiewicz, Adam Wiatkowski, Urszula Szwedowicz, Anna Choromańska.

  Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

Keywords:  cancer stem cells; glycolysis; hexokinase; lactate dehydrogenase A; phosphofructokinase; pyruvate kinase; the Warburg effect; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms26051879
Front Mol Biosci. 2025 ;12 1574538

Editorial: Role of fibroblast in cancer.

Xuezhen Zeng, Man Liu.



Keywords:  ); cancer; cancer associated fibroblast (CAF); fibroblast; therapy; tumor microenvironment (TME

DOI:  https://doi.org/10.3389/fmolb.2025.1574538
Cancer Discov. 2025 Mar 12.

RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.

Augusto Bleve, Martina Incerti, Francesca Maria Consonni, Valentina Garlatti, Giulia Ballerini, Chiara Pandolfo, Marta Noemi Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Elettra Barberis, Giovanna Finocchiaro, Marco Antonio Cassatella, Cristina Panico, Gianluigi Condorelli, Antonio Sica.

Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic-acid-related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0199
Biomark Res. 2025 Mar 11. 13(1): 41

Nanobody-enhanced chimeric antigen receptor T-cell therapy: overcoming barriers in solid tumors with VHH and VNAR-based constructs.

Shasha Guo, Xiaozhi Xi.

  CAR-T cells are genetically modified T lymphocytes that express chimeric antigen receptors (CAR) on their surfaces. These receptors enable T lymphocytes to recognize specific antigens on target cells, triggering a response that leads to targeted cytotoxicity. While CAR-T therapy has effectively treated various blood cancers, it faces significant challenges in addressing solid tumors. These challenges include identifying precise tumor antigens, overcoming antigen evasion, and enhancing the function of CAR-T cells within the tumor microenvironment. Single domain antibody, versatile tools with low immunogenicity, high stability, and strong affinity, show promise for improving the efficacy of CAR-T cells against solid tumors. By addressing these challenges, single domain antibody has the potential to overcome the limitations associated with ScFv antibody-based CAR-T therapies. This review highlights the benefits of utilizing single domain antibody in CAR-T therapy, particularly in targeting tumor antigens, and explores development strategies that could advance the field.

Keywords:  CAR-T; Single domain antibody; Solid tumor; VHH; VNAR

DOI:  https://doi.org/10.1186/s40364-025-00755-5
Cancer Lett. 2025 Mar 05. pii: S0304-3835(25)00177-6. [Epub ahead of print]617 217613

Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.

Si Lu, Qimin Zhou, Rongjie Zhao, Lei Xie, Wen-Ming Cao, Yu-Xiong Feng.

  Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.

Keywords:  Immunotherapy resistance; Tumor microenvironment; UPR

DOI:  https://doi.org/10.1016/j.canlet.2025.217613
Int J Biol Sci. 2025 ;21(5): 2235-2257

Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets.

Huabing Tan, Meihe Cai, Jincheng Wang, Tao Yu, Houjun Xia, Huanbin Zhao, Xiaoyu Zhang.

  Macrophages, as the predominant phagocytes, play an essential role in pathogens defense and tissue homeostasis maintenance. In the context of cancer, tumor-associated macrophages (TAMs) have evolved into cunning actors involved in angiogenesis, cancer cell proliferation and metastasis, as well as the construction of immunosuppressive microenvironment. Once properly activated, macrophages can kill tumor cells directly through phagocytosis or attack tumor cells indirectly by stimulating innate and adaptive immunity. Thus, the prospect of targeting TAMs has sparked significant interest and emerged as a promising strategy in immunotherapy. In this review, we summarize the diverse roles and underlying mechanisms of TAMs in cancer development and immunity and highlight the TAM-based therapeutic strategies such as inhibiting macrophage recruitment, inhibiting the differentiation reprogramming of TAMs, blocking phagocytotic checkpoints, inducing trained macrophages, as well as the potential of engineered CAR-armed macrophages in cancer therapy.

Keywords:  cancer immunity; immunotherapy; macrophage; phagocytotic checkpoint; trained macrophage

DOI:  https://doi.org/10.7150/ijbs.106275
Cell Death Discov. 2025 Mar 11. 11(1): 94

Ex.50.T aptamer impairs tumor-stroma cross-talk in breast cancer by targeting gremlin-1.

Cristina Quintavalle, Francesco Ingenito, Giuseppina Roscigno, Birlipta Pattanayak, Carla Lucia Esposito, Alessandra Affinito, Danilo Fiore, Gianluca Petrillo, Silvia Nuzzo, Bartolomeo Della Ventura, Federica D'Aria, Concetta Giancola, Stefania Mitola, Elisabetta Grillo, Marinella Pirozzi, Greta Donati, Francesco Saverio Di Leva, Luciana Marinelli, Zoran Minic, Francesca De Micco, Guglielmo Thomas, Maxim V Berezovski, Gerolama Condorelli.

The tumor microenvironment profoundly influences tumor complexity, particularly in breast cancer, where cancer-associated fibroblasts play pivotal roles in tumor progression and therapy resistance. Extracellular vesicles are involved in mediating communication within the TME, specifically highlighting their role in promoting the transformation of normal fibroblasts into cancer-associated fibroblasts. Recently, we identified an RNA aptamer, namely ex.50.T, that binds with remarkable affinity to extracellular vesicles shed from triple-negative breast cancer cells. Here, through in vitro assays and computational analyses, we demonstrate that the binding of ex.50.T to extracellular vesicles and parental breast cancer cells is mediated by recognition of gremlin-1 (GREM1), a bone morphogenic protein antagonist implicated in breast cancer aggressiveness and metastasis. Functionally, we uncover the role of ex.50.T as an innovative therapeutic agent in the process of tumor microenvironment re-modeling, impeding GREM1 signaling, blocking triple-negative breast cancer extracellular vesicles internalization in recipient cells, and counteracting the transformation of normal fibroblasts into cancer-associated fibroblasts. Altogether, our findings highlight ex.50.T as a novel therapeutical avenue for breast cancer and potentially other GREM1-dependent malignancies, offering insights into disrupting TME dynamics and enhancing cancer treatment strategies.

DOI: https://doi.org/10.1038/s41420-025-02363-6
Mol Cancer. 2025 Mar 08. 24(1): 71

Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications.

Xiaowen Xie, Weici Liu, Zhiyuan Yuan, Hanqing Chen, Wenjun Mao.

  Epigenomic modifications-such as DNA methylation, histone acetylation, and histone methylation-and their implications in tumorigenesis, progression, and treatment have emerged as a pivotal field in cancer research. Tumors undergo metabolic reprogramming to sustain proliferation and metastasis in nutrient-deficient conditions, while suppressing anti-tumor immunity in the tumor microenvironment (TME). Concurrently, immune cells within the immunosuppressive TME undergo metabolic adaptations, leading to alterations in their immune function. The complicated interplay between metabolites and epigenomic modulation has spotlighted the significance of epigenomic regulation in tumor immunometabolism. In this review, characteristics of the epigenomic modification associated with tumors are systematically summarized alongside with their regulatory roles in tumor metabolic reprogramming and immunometabolism. Classical and emerging approaches are delineated to broaden the boundaries of research on the crosstalk research on the crosstalk between tumor immunometabolism and epigenomics. Furthermore, we discuss potential therapeutic strategies that target tumor immunometabolism to modulate epigenomic modifications, highlighting the burgeoning synergy between metabolic therapies and immunotherapy as a promising avenue for cancer treatment.

Keywords:  Cancer treatment; Epigenomics; Immunometabolism; Metabolic reprogramming; ScATAC-seq; Spatial metabolomics; Tumor

DOI:  https://doi.org/10.1186/s12943-025-02269-y
Cancer Med. 2025 Mar;14(5): e70622

Analyze the Diversity and Function of Immune Cells in the Tumor Microenvironment From the Perspective of Single-Cell RNA Sequencing.

Lujuan Ma, Yu Luan, Lin Lu.

   BACKGROUND: Cancer development is closely associated with complex alterations in the tumor microenvironment (TME). Among these, immune cells within the TME play a huge role in personalized tumor diagnosis and treatment.
OBJECTIVES: This review aims to summarize the diversity of immune cells in the TME, their impact on patient prognosis and treatment response, and the contributions of single-cell RNA sequencing (scRNA-seq) in understanding their functional heterogeneity.
METHODS: We analyzed recent studies utilizing scRNA-seq to investigate immune cell populations in the TME, focusing on their interactions and regulatory mechanisms.
RESULTS: ScRNA-seq reveals the functional heterogeneity of immune cells, enhances our understanding of their role in tumor antibody responses, and facilitates the construction of immune cell interaction networks. These insights provide guidance for the development of cancer immunotherapies and personalized treatment approaches.
CONCLUSION: Applying scRNA-seq to immune cell analysis in the TME offers a novel pathway for personalized cancer treatment. Despite its promise, several challenges remain, highlighting the need for further advancements to fully integrate scRNA-seq into clinical applications.

Keywords:  cancer; immune cells; single‐cell sequencing; tumor microenvironment

DOI:  https://doi.org/10.1002/cam4.70622
Cell Immunol. 2025 Mar 01. pii: S0008-8749(25)00019-X. [Epub ahead of print]411-412 104934

Divergent impact of endotoxin priming and endotoxin tolerance on macrophage responses to cancer cells.

Konkonika Roy, Tomasz Jędrzejewski, Justyna Sobocińska, Paulina Spisz, Bartosz Maciejewski, Nadine Hövelmeyer, Benedetta Passeri, Sylwia Wrotek.

  Endotoxin tolerance (ET) is an adaptive phenomenon that arises from the repeated exposure of immune cells, such as macrophages, to endotoxins like lipopolysaccharide (LPS). Initially, when macrophages are activated by LPS, they produce inflammatory mediators that drive the primary immune response. However, this response is significantly diminished during the establishment of ET, creating an immunosuppressive environment. This environment can facilitate the development and progression of malignant conditions, including cancer. Our research focused on the interactions between immune cells and the tumor microenvironment under ET conditions. Through comprehensive in vivo and in vitro studies employing various research techniques, we have demonstrated that interactions between endotoxin-tolerant macrophages (MoET) and cancer cells contribute to a pro-tumorigenic condition. Notably, we observed that MoET adapt a pro-tumorigenic, immunosuppressive M2 phenotype (CD163 expression). These macrophages involves distinct metabolic pathways, not depending solely on glycolysis and oxidative phosphorylation. Furthermore, our in vivo findings revealed macrophage infiltration within tumors under both ET and non-ET conditions, highlighting the suppressed immune landscape in the presence of ET. These findings suggest that ET plays a pivotal role in shaping tumor-associated immune responses and that targeting ET pathways could offer a novel and promising therapeutic approach for cancer treatment.

Keywords:  Endotoxin tolerance; Immunosuppression; M1/M2 phenotype; Tumor microenvironment; cancer

DOI:  https://doi.org/10.1016/j.cellimm.2025.104934
Cancer Cell Int. 2025 Mar 07. 25(1): 82

Integrating spatial and single-cell transcriptomes reveals the role of COL1A2(+) MMP1(+/-) cancer-associated fibroblasts in ER-positive breast cancer.

Zhi-Hao Yu, Huan-Ling Xu, Shuo Wang, Ying-Xi Li, Gui-Xin Wang, Yao Tian, Zhao-Hui Chen, Wen-Bin Song, Long He, Xin Wang, Xu-Chen Cao, Yue Yu.

  Cancer-associated fibroblasts (CAFs) are highly heterogeneous cells and important components of the breast tumor microenvironment (TME). However, their role and clinical value in ER-positive breast cancer have not been fully clarified. Our study aims to comprehensively characterize the heterogeneity, potential biological functions, and molecular mechanisms of CAFs in ER-positive breast cancer within the tumor microenvironment using multi-omics data, to provide new strategies for the diagnosis and treatment of ER-positive breast cancer patients. In this study, we found that COL1A2(+) MMP1(+) and COL1A2(+) MMP1(-) CAFs were associated with unfavorable prognosis. The dynamic evolution and cell-cell communications of CAFs were analyzed, revealing that COL1A2(+) MMP1(+/-) CAFs show extensive crosstalk with tumor-associated macrophages (TAMs), contributing to an immunosuppressive TME. Moreover, the somatic mutation of TP53 may be a potential indicator for evaluating the infiltration of COL1A2(+) MMP1(+/-) CAFs. Finally, an MRI-based radiomic model was constructed to estimate the abundance of these CAFs. In conclusion, our findings provide a theoretical basis for targeting CAFs and offer a noninvasive approach to evaluate the infiltration level of COL1A2(+) MMP1(+/-) CAFs.

Keywords:  Cancer-associated fibroblasts; ER-positive breast cancer; Radiomics; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-03705-1
Front Immunol. 2025 ;16 1556209

The role of tumor-associated macrophages in lung cancer.

Ronghao Zhu, Jing Huang, Fenhong Qian.

  Lung cancer remains a leading cause of cancer-related deaths worldwide, necessitating innovative treatments. Tumor-associated macrophages (TAMs) are primary immunosuppressive effectors that foster tumor proliferation, angiogenesis, metastasis, and resistance to therapy. They are broadly categorized into proinflammatory M1 and tumor-promoting M2 phenotypes, with elevated M2 infiltration correlating with poor prognosis. Strategies aimed at inhibiting TAM recruitment, depleting TAMs, or reprogramming M2 to M1 are therefore highly promising. Key signaling pathways, such as CSF-1/CSF-1R, IL-4/IL-13-STAT6, TLRs, and CD47-SIRPα, regulate TAM polarization. Additionally, macrophage-based drug delivery systems permit targeted agent transport to hypoxic regions, enhancing therapy. Preclinical studies combining TAM-targeted therapies with chemotherapy or immune checkpoint inhibitors have yielded improved responses and prolonged survival. Several clinical trials have also reported benefits in previously unresponsive patients. Future work should clarify the roles of macrophage-derived exosomes, cytokines, and additional mediators in shaping the immunosuppressive tumor microenvironment. These insights will inform the design of next-generation drug carriers and optimize combination immunotherapies within precision medicine frameworks. Elucidating TAM phenotypes and their regulatory molecules remains central to developing novel strategies that curb tumor progression and ultimately improve outcomes in lung cancer. Importantly, macrophage-based immunomodulation may offer expanded treatment avenues.

Keywords:  TAMs; immunomodulation; immunotherapy; lung cancer; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1556209