bims-flamet 2025-12-28 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–12–28
thirty-one papers selected by
Peio Azcoaga, Biodonostia HRI

The Role of Macrophages in Cancer: From Basic Research to Clinical Applications.
SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications.
The emerging role of dendritic cells in the tumor microenvironment: from antigen presentation to targeted immunotherapy.
Endothelial Cells in Lymphomas.
Post-translational modifications of proteins: dynamic regulatory network and therapeutic targets of tumor immune escape in pan-cancer.
Interaction of intratumoral microbiota with the tumor immune microenvironment and its impact on cancer progression.
Macrophage-cancer cell crosstalk in breast cancer chemotherapy resistance.
Cancer-Associated Fibroblasts-Derived Exosomes as Mediators of Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma.
RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation.
Targeting STING to generate therapeutic anti-tumor immunity.
Cancer-associated fibroblasts at the crossroads of tumor progression and therapy resistance: from heterogeneity to precision reprogramming.
Dauricine Inhibits Macrophages M2 Polarization and Regulates the Progression and Ferroptosis via HCK/IDO1 in Urinary Bladder Cancer.
Advances in nanomedicine strategies for modulating the tumor microenvironment: Recent progress and clinical perspectives.
Therapeutic potential of microRNA let-7a-enriched exosomes in modulating macrophage plasticity (M1) and inhibiting malignant tendencies in breast cancer.
Chronic compression induces transcriptional, metabolic, and functional state changes in macrophages that recapitulate tumor-associated phenotypes.
Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.
Cytotoxic CD4+ T cells in cancer: an emerging target for next-generation anticancer immunotherapy?
Mast Cells in the Solid Tumor Microenvironment: Multiple Roles and Targeted Therapeutic Potential.
Mechano-regulation of cancer cell memory in tumor progression and therapy.
Sirtuins and tumor immunity: mechanistic insights, immunotherapy prospects, and therapeutic horizons.
Inhibin beta A drives colorectal cancer progression through macrophage M2 polarization and mitochondria-dependent ferroptosis suppression.
Cancer-Associated Fibroblasts: Clinical Applications in Imaging and Therapy.
IL-37/IL-1R8 axis: a novel major mechanism of control at the interface between tumor and immune cells.
Immune and non-immune cell fencing of tumor cells is a widespread and functionally relevant spatial pattern in solid cancers.
The dual role of autophagy in breast cancer stemness and treatment resistance.
Immune archetypes TIME classification system for nasopharyngeal carcinoma: A new direction for precision immunotherapy.
Interferons as therapeutic orchestrators of cancer stem cell plasticity and therapy response.
Macrophages in Colorectal Cancer: from Normal Mucosa to Distant Metastasis: Beyond the M1/M2 Paradigm.
Using Mathematical Modeling of Tumor Metabolism to Predict the Magnitude, Composition, and Hypoxic Interactions of Microenvironment Acidosis.
CHS-114: an afucosylated anti-CCR8 monoclonal antibody that selectively depletes intratumoral Treg cells and induces antitumor immune responses.
Unraveling Immunotherapy Resistance in Solid Tumors: Decoding Mechanisms and Charting Future Therapeutic Landscapes.

MedComm (2020). 2026 Jan;7(1): e70547

The Role of Macrophages in Cancer: From Basic Research to Clinical Applications.

Zhimei Liu, Yan Li, Jingchao Cao, Yefeng Qiu, Kun Yu, Shoulong Deng.

  Macrophages are innate immune cells that extensively infiltrate and play a key role in the tumor microenvironment (TME). Tumor cell-secreted factors recruit monocytes into the TME, where they differentiate into tumor-associated macrophages (TAMs), which can polarize into distinct phenotypes: M1 and M2. M1 TAMs promote antitumor immunity through cytokine secretion and antigen presentation, whereas M2 TAMs support tumor progression by facilitating angiogenesis, invasion, and immune escape. Despite these dual roles, the specific mechanisms governing macrophage plasticity and polarization remain insufficiently understood. This review comprehensively summarizes the origin, polarization, and functional diversity of macrophages in the TME, with emphasis on pathways that regulate TAM-mediated immune responses. Furthermore, this article examines current TAM-targeted therapeutic strategies, including recruitment inhibition, phenotypic reprogramming, and the development of chimeric antigen receptor macrophages (CAR-Ms), as well as macrophage-based drug delivery and exosome therapy. By integrating recent advances in cell engineering and immunometabolism, this review highlights the translational potential of TAM-targeted therapies and their value in reshaping the immunosuppressive TME to enhance cancer immunotherapy.

Keywords:  CAR‐M; cell therapy; macrophages; tumor microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/mco2.70547
Front Immunol. 2025 ;16 1711015

SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications.

Juanjuan Wang, Ya Wang, Yuqing Liu, Rongcun Yang.

  Secreted phosphoprotein 1 (SPP1+) macrophages are a recurrent and functionally critical immune cell subset across multiple cancer types. They drive adverse clinical outcomes by promoting immunosuppression, tumor invasion, metastasis, and therapy resistance. Given their prevalence and pivotal role, SPP1+ macrophages have become a major focus in cancer immunology and a promising target for therapeutic development. SPP1+ macrophages have been identified in a wide range of human malignancies through single-cell RNA sequencing and spatial transcriptomics studies. Their differentiation and maintenance are strongly influenced by reciprocal cellular interactions and hypoxic conditions within the tumor microenvironment (TME). Within the tumor microenvironment (TME), SPP1+ macrophages promote tumor progression by interacting with cancer-associated fibroblasts (CAFs) and helping to form a physical barrier that restricts immune cell infiltration into the tumor core. Specifically, they impair the recruitment of CD8+ T cells and promote T cell exhaustion (TEX). In this review, we focus on recent advances in understanding the differentiation of SPP1 macrophages in hypoxic tumor microenvironment and the role of SPP1+ macrophages in immunosuppression and their therapeutic implications in cancer. Targeting this subset of macrophages has emerged as a highly promising therapeutic strategy, with several approaches demonstrating encouraging results in preclinical models.

Keywords:  SPP1+ macrophages; T cell exhaustion; cancer therapy; osteopontin; physical barrier

DOI:  https://doi.org/10.3389/fimmu.2025.1711015
Cell Death Dis. 2025 Dec 22. 16(1): 900

The emerging role of dendritic cells in the tumor microenvironment: from antigen presentation to targeted immunotherapy.

Zhiyuan Xie, Yingjun Fang, Xinhao Zhang, Yingshuai Fang, Ruiqi Li, Ying Guo, Yabing Yang, Shuaixi Yang, Lijie Song.

Dendritic cells (DCs), as pivotal antigen-presenting cells (APCs), play crucial roles in initiating T cell-mediated antitumor immune responses, bridging innate and adaptive immunity while maintaining immune tolerance. With an in-depth understanding of DC biology and functions, numerous DC-targeted therapeutic approaches have been developed. An enhanced understanding of DC heterogeneity and DC cross-talk with other cells within the tumor microenvironment (TME), along with functional and metabolic remodeling mechanisms, may optimize DC-based cancer immunotherapies. This review focuses on the heterogeneity of the individual occurrence and function of DCs in tumors, elucidates the cross-talk between DCs and other cells in the TME, provides an in-depth understanding of the dysfunction and metabolic reprogramming of DCs in the TME, and summarizes existing DC-based anticancer therapies and novel therapeutic strategies, with the aim of providing new insight into the emerging role of DCs in future cancer immunotherapy.

DOI: https://doi.org/10.1038/s41419-025-08180-0
Eur J Haematol. 2025 Dec 22.

Endothelial Cells in Lymphomas.

Domenico Ribatti.

  Endothelial cells play a complex role in lymphoma by becoming genetically abnormal alongside tumor cells, forming blood vessels that fuel lymphoma growth and invasiveness, and contributing to the establishment of an immunosuppressive tumor microenvironment. Because of their significant role in lymphoma growth and immune evasion, endothelial cells and the processes that regulate them are being explored as attractive targets for new anti-angiogenic therapies and immunotherapies to overcome the limitations of anti-angiogenic therapy in lymphoma treatment.

Keywords:  angiogenesis; anti‐angiogenesis; endothelium; lymphoma; tumor progression

DOI:  https://doi.org/10.1111/ejh.70089
Crit Rev Clin Lab Sci. 2025 Dec 24. 1-34

Post-translational modifications of proteins: dynamic regulatory network and therapeutic targets of tumor immune escape in pan-cancer.

Qilu Yan, Qingqing Zhai, Shuyang Yu, Wangzheqi Zhang.

  Post-translational modifications (PTMs) are critical regulators of protein function. Nearly two-thirds of all human proteins contain at least one PTM. These PTMs introduce covalent modifications, which modulate protein activity, location, and interactions. Further, PTMs are essential for understanding both physiological homeostasis and pathophysiology, and they play a key role in tumorigenesis and cancer development. Tumor immune evasion depends on dysregulated immune homeostasis caused by interactions between tumor cells and immune cells in the tumor microenvironment (TME). In this context, PTMs have emerged as one of the key regulators. From a pan-cancer perspective, PTMs remodel the tumor immune microenvironment through diverse mechanisms. The inability to regulate these processes is a common factor contributing to immune evasion in various cancers. It also facilitates crosstalk between tumor cells and components of TME, which in turn influences the response to immunotherapy. Because PTMs are dysregulated in cancers and can be reversed through drugs, they are attractive therapeutic targets. Small-molecule modulators of PTMs have the potential to reprogram the immune microenvironment and improve immune checkpoint blockade responses. Importantly, wide-ranging signal exchange networks between PTMs collectively increase tumoral immune phenotypic diversity and reveal new shared mechanisms of pan-cancer immune evasion. Recent studies show that the ways tumor cells change their surface proteins are driven by alterations in the tumor-immune environment. Further work could lead to strategies to treat many different cancers. Targeting PTM networks may overcome immune tolerance and significantly improve the clinical prognosis of cancer patients.

Keywords:  PTMs; Post-translational modifications; antigen presentation; crosstalk mechanism; dynamic regulation; pan-cancer; tumor immune evasion

DOI:  https://doi.org/10.1080/10408363.2025.2598380
Front Oncol. 2025 ;15 1609889

Interaction of intratumoral microbiota with the tumor immune microenvironment and its impact on cancer progression.

Yan Tingting, Zhu Xiaoling, Zhang Yu, Luo Yan, Luo Yang, Shang Xueqin, Tang Shikai.

  The intratumoral microbiota, a critical component of the tumor microenvironment (TME), has been demonstrated to significantly impact tumor progression and therapeutic outcomes. Research indicates that intratumoral microbes can affect tumorigenesis, metastasis, and therapeutic response through various mechanisms, such as inducing DNA damage, activating oncogenic signaling pathways, and modulating immune responses. Furthermore, the microbiota exerts dual regulatory effects on the tumor immune microenvironment (TIME), either enhancing anti-tumor immunity or promoting immunosuppression, thereby presenting novel targets for cancer therapy. In this paper, we conduct a review of the origin and composition of the intratumoral microbiota and its dynamic interactions with the TME by synthesizing data from multiple cancer studies. This review elucidates the complex role of the microbiota within the TIME and explores its potential for clinical application.

Keywords:  antitumor immunity; immune cells; immunosuppression; intratumoral microbiota; tumor immune microenvironment; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1609889
Med Oncol. 2025 Dec 24. 43(2): 63

Macrophage-cancer cell crosstalk in breast cancer chemotherapy resistance.

A I Guo, Li-Hui Gu, Yi-Yue Ding, Xue-Jie Wang, Hong-Xing Zhang, Zhi-Mei Sheng, Rong-Shuo Zhang, Xue-Jun Dong, Wan-Li Duan, Bao-Gang Zhang.

  Breast cancer (BC) represents one of the most prevalent malignancies in the female population and constitutes a leading cause of cancer-associated mortality among women globally. The emergence of chemoresistance persists as a critical challenge in current breast cancer therapeutic strategies. Malignant tumors are enveloped by a sophisticated assemblage of cellular and non-cellular components that collectively establish the tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), being one of the most abundant immune infiltrates within the TME, have been demonstrated to play an instrumental role in the development and progression of chemotherapeutic resistance mechanisms. Recent studies have revealed that TAMs and breast cancer cells engage in complex bidirectional interactions. This crosstalk not only facilitates tumor immune evasion but also promotes chemotherapy resistance in breast cancer through the secretion of various cytokines, chemokines, growth factors, and other bioactive molecules. Therefore, elucidating the underlying mechanisms by which TAMs contribute to chemotherapy resistance is of significant importance. This review summarizes the dynamic and bidirectional regulatory network formed between TAMs and BC. Centering on this network, it comprehensively analyzes the molecular mechanisms by which TAMs regulate chemotherapy resistance in BC, summarizes potential targeted drugs that disrupt molecular interactions between TAMs and BC, and discusses the therapeutic prospects of combining these drugs with chemotherapy and immunotherapy. The findings aim to provide novel insights into potential molecular targets for overcoming chemotherapy resistance and to explore new therapeutic strategies for breast cancer patients.

Keywords:  Breast cancer; Chemotherapy resistance; Macrophages; Molecular mechanisms; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-025-03161-x
Cells. 2025 Dec 12. pii: 1978. [Epub ahead of print]14(24):

Cancer-Associated Fibroblasts-Derived Exosomes as Mediators of Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma.

Julia Federspiel, Jozsef Dudas, Benedikt Gabriel Hofauer, Barbara Wollenberg, Teresa Bernadette Steinbichler.

  The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8+ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial-mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME.

Keywords:  EMT; PD-L1 inhibitors; cancer-associated fibroblasts; exosomes; tumor microenvironment

DOI:  https://doi.org/10.3390/cells14241978
NPJ Precis Oncol. 2025 Dec 23.

RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation.

Yan Zhou, Huan Gao, Liyu Shan, Lizhe Zhu, Jiao Yang, Bo Wang, Juan Zhang, Ran Ran, Qi Tian, Peijun Liu, Jin Yang.

Immunotherapy has emerged as an effective treatment for breast cancer, making the exploration of novel immune-related biomarkers of paramount importance. A vital aspect of this exploration is the investigation into the subtyping of tumor-associated macrophages (TAMs). While polarity proteins within TAMs can shift their functional status, the impact of polarity proteins on inflammation-related signaling in tumor cells and their subsequent influence on the tumor microenvironment (TME) remains elucidated. We discovered that RICH1, functioning as a tumor suppressor molecule in breast cancer, significantly increased the infiltration of pro-inflammatory M1-like TAMs within TME in 4T1 tumor-bearing mice. Furthermore, the conditioned medium from RICH1-overexpressing 4T1 cells promoted M1-like polarization in vitro by stimulating the secretion of IFN-γ and other cytokines. Mechanistically, high expression of RICH1 in breast cancer cells facilitated the ubiquitination degradation of RhoA through binding with TRIM21 and enhancing the interaction between TRIM21-RhoA, thereby inhibited the phosphorylation of STAT3, up-regulated the production and secretion of IFN-γ, consequently induced M1-like polarization of macrophages. Our findings reveal that RICH1 plays a crucial role in promoting pro-inflammatory TAMs infiltration in breast cancer through modulation of inflammatory signaling. These results suggest that RICH1 could serve as an immune-related biomarker and a key contributor to the formation of immune-active microenvironments, with potential applications in combination immunotherapy strategies.

DOI: https://doi.org/10.1038/s41698-025-01252-6
Cancer Cell. 2025 Dec 24. pii: S1535-6108(25)00536-7. [Epub ahead of print]

Targeting STING to generate therapeutic anti-tumor immunity.

Caroline G Fahey, Anthony F Cordova, Patrick C Gedeon, David A Barbie.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.

Keywords:  STING; anti-tumor immunity; cGAS; innate immunity; interferon; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.12.002
J Egypt Natl Canc Inst. 2025 Dec 22. 37(1): 81

Cancer-associated fibroblasts at the crossroads of tumor progression and therapy resistance: from heterogeneity to precision reprogramming.

Ravi Adusumalli, Rajkiran Reddy Banala.



Keywords:  Cancer-associated fibroblasts (CAFs); Fibroblast heterogeneity; Immune evasion; Precision oncology; Stromal reprogramming; Therapy resistance; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s43046-025-00334-7
Food Sci Nutr. 2025 Dec;13(12): e71341

Dauricine Inhibits Macrophages M2 Polarization and Regulates the Progression and Ferroptosis via HCK/IDO1 in Urinary Bladder Cancer.

Jie Gong, Dianyu Sun, Yuxin Zheng, Chuwen Mao, Bowen Yu, Xiaogang Li, Yanhua Xuan.

  Tumor-associated macrophages (TAMs), particularly the M2 phenotype, have the ability to promote malignant tumor progression and metastasis. Dauricine (DAU) is a Chinese herbal monomer that has been shown to have inhibitory effects on various tumor cells. However, the mechanisms by which DAU influences tumor microenvironment and bladder cancer (BLCA) progression remain unclear. Herein, we investigated the effects of DAU on macrophage M2 polarization and BLCA progression. In this study, besides demonstrating that DAU can mediate the inhibition of macrophage M2 polarization and promote macrophage ferroptosis induced by BLCA cell supernatants via HCK, we further verified that DAU regulated IDO1, which is downstream of HCK, to affect the M2-like TAMs induced by BLCA progression and ferroptosis. In addition, we also observed an increase in ferritinophagy in BLCA cells under DAU treatment. These findings reveal an unsuspected function of DAU in inhibiting malignant progression of BLCA by interfering with M2 polarization and ferroptosis in TAMs through the HCK/IDO1 axis.

Keywords:  bladder cancer; chinese medicine monomer; dauricine; ferroptosis; macrophage

DOI:  https://doi.org/10.1002/fsn3.71341
3 Biotech. 2026 Jan;16(1): 36

Advances in nanomedicine strategies for modulating the tumor microenvironment: Recent progress and clinical perspectives.

Talha Bin Emran, Md Al Amin, Safia Obaidur Rab, Patibandla Jahnavi, Rajeshwar Vodeti, Jeetendra Kumar Gupta, Uppuluri Varuna Naga Venkata Arjun, T N Umamaheswari, P Balaji, Girija Dayalan, Soniya Rani, Prem Shankar Gupta.

  The tumor microenvironment (TME) significantly impacts tumor development, metastasis, immune evasion, and resistance to conventional treatments. Recent nanomedicine advancements aid the formation of intelligent, multipurpose nanosystems that precisely target and modify various TME elements, including hypoxia, extracellular matrix, tumor-associated macrophages, and immunological checkpoints. The review highlights recent advancements in nanotechnology-based methods for optimizing medication delivery, renewing the TME, and enhancing treatment outcomes. It discusses the impact of nanomedicines on the TME, including immune modulation, stimuli-responsive drug release, and the restoration of abnormal vasculature. It also demonstrates the translational landscape of these methods, focusing on safety profiles, clinical trials, and scaling challenges from preclinical models to clinical applications. Nanomedicine offers personalized cancer treatments by regulating tumor TME, enhancing immunity, restoring tumor vasculature, and targeting multiple TME components through smart nanocarriers. Combination approaches with immunotherapy, photothermal therapy, and chemotherapy show synergistic results. Clinical trials show promise but face scalability and reproducibility issues.

Keywords:  Immune modulation; Nanomedicine; Stimuli-responsive nanoparticles; Targeted drug delivery; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13205-025-04651-5
Eur J Pharmacol. 2025 Dec 18. pii: S0014-2999(25)01255-5. [Epub ahead of print]1012 178501

Therapeutic potential of microRNA let-7a-enriched exosomes in modulating macrophage plasticity (M1) and inhibiting malignant tendencies in breast cancer.

Elmira Aghazadeh, Shahla Mohammad Ganji, Fatemeh Ashrafi, Ardeshir Abbasi.

  Tumor-associated macrophages (TAMs) play a pivotal role in cancer progression, and their polarization toward the M2 phenotype contributes to immune suppression and metastasis promotion. One promising immunotherapeutic approach involves reprogramming M2 macrophages into the pro-inflammatory and anti-tumor M1 phenotype within the tumor microenvironment. This study investigated the effect of exosomes derived from 4T1 breast cancer cells, loaded with microRNA let-7a, on macrophage polarization and tumor-related behaviors. Tumor-derived exosomes (TEXs) were isolated and characterized by DLS, Flowcytometry (CD63) and TEM, followed by let-7a loading via electroporation. Peritoneal macrophages from Balb/c mice were extracted, polarized into the immunosuppressive M2 phenotype, and subsequently treated with let-7a -enriched exosomes (TEX + let-7a), leading to their repolarization into M1 macrophages. Anti-cancer assays, including viability, apoptosis, metastasis, angiogenesis, and migration, were then performed. Results demonstrated that these engineered exosomes effectively repolarized M2 macrophages into active, tumor-suppressing M1 macrophages. The induced M1 macrophages significantly reduced cancer cell survival, increased apoptosis through elevated BAX/Bcl-2 ratio, and suppressed the expression of metastasis-associated (MMP2, MMP9) and angiogenesis-related (VEGF) genes. Moreover, cancer cell migration was markedly inhibited. Collectively, these findings indicate that let-7a -enriched exosomes can reprogram macrophage plasticity to effectively suppress malignant behaviors in breast cancer. This novel approach highlights the high therapeutic potential of targeted exosome-based miRNA delivery for refining tumor microenvironment regulation and advancing breast cancer immunotherapy strategies.

Keywords:  Breast cancer; Cancer immunotherapy; Exosomes; Let-7a; Macrophage polarization

DOI:  https://doi.org/10.1016/j.ejphar.2025.178501
Front Immunol. 2025 ;16 1626024

Chronic compression induces transcriptional, metabolic, and functional state changes in macrophages that recapitulate tumor-associated phenotypes.

Alice Burchett Darantiere, Hao Chen, Julian Najera, Scott Howard, Meenal Datta.

   Introduction: Macrophages comprise a significant portion of the glioblastoma tumor microenvironment and are essential in promoting immunosuppression and tumor progression. Solid tumors such as glioblastoma generate solid stress as they expand, creating a compressive microenvironment for mechanosensitive immune cells including macrophages. Macrophages are known to respond to various mechanical stimuli but have not yet been studied in the context of chronic compression observed in growing tumors.
Methods: Here, we used a custom in vitro compression system to elucidate the effects of compressive solid stress on murine macrophages.
Results: We found that macrophages have significant morphological, transcriptional, metabolic, and functional responses to compression. These changes corresponded to both canonical pro- and anti-inflammatory macrophage states. The gene expression signatures of compressed macrophages more closely resembled those of glioma-associated macrophages known to be associated with worse patient outcomes.
Conclusion: These results indicate that compression alone, independent from tumor cell-derived biochemical factors, may contribute to the pathological tumor-associated macrophage phenotype. This could represent a vicious cycle of tumor immunomechanics and mechano-immunology. Targeting solid stress in tumors or the response to solid stress by macrophages may interrupt this feedback loop to help normalize the tumor immune microenvironment and improve glioblastoma response to immunotherapy.

Keywords:  Myeloid cells; fluorescence lifetime imaging (FLIM); glioblastoma.; immunomechanics; mechano-immunology; metabolism; polarization; solid stress

DOI:  https://doi.org/10.3389/fimmu.2025.1626024
Eur J Pharmacol. 2025 Dec 24. pii: S0014-2999(25)01264-6. [Epub ahead of print] 178510

Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.

Ping Ye, Mingjun Sun, Jia Wang, Xianzhao Bai, Zihan Li, Qiang Lin, Ran Liu.

  Exosomes, small endosome-derived vesicles, mediate intercellular crosstalk among cancer cells within the tumor microenvironment (TME), while metabolic reprogramming directly drives these phenotypic changes. Recently, the application of nanoparticle tracking analysis and mass spectrometry to exosome identification and metabolite detection has brought exosome-loaded metabolites in the TME into sharp research focus. In this study, we compared the exosomal metabolites derived from cancer versus normal cells, and elucidated how these differences modulate communication between tumor and stromal or immune cells. The differences in oncometabolites associated with tumors mainly include changes in fatty acids and amino acids. Tumor metabolic shifts reflected by exosomal amino-acids alterations center on glutamate metabolism and arginine biosynthesis. Tumor-associated alterations in exosomal fatty acids centered around the biosynthesis and metabolism of phosphatidylcholine and ceramide. Like nucleic acids and proteins, exosomal metabolites serve as non-invasive, efficient biomarkers for cancer detection.

Keywords:  Exosomal metabolites; Intercellular communication; Precision therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ejphar.2025.178510
J Immunother Cancer. 2025 Dec 23. pii: e013461. [Epub ahead of print]13(12):

Cytotoxic CD4+ T cells in cancer: an emerging target for next-generation anticancer immunotherapy?

Imke M B van Wandeloo, Kalijn Bol, Carla van Herpen, I Jolanda M de Vries, Gerty Schreibelt.

  Over the last decades, a growing number of distinct CD4+T helper cells has been identified and our understanding of CD4+T cell differentiation and function in various disease contexts has increased immensely. It has long been thought that the role of CD4+T cells in the tumor microenvironment (TME) was limited to coordinating the immune response by stimulating other immune cells and by secretion of cytokines with antitumor activity, while direct killing of tumor cells has been largely attributed to cytotoxic CD8+T cells. Notably, CD4+T cells with direct cytotoxic activity (CD4+CTLs) have been reported in the context of viral infections, autoimmune disorders, and more recently in patients with various cancer types. These cells have the ability to secrete cytotoxic molecules and kill target cells in a major histocompatibility complex (MHC) class II-dependent manner. In this review, we give an overview of phenotypical characteristics of CD4+CTLs in human cancers and the antitumor mechanisms employed by these cells. Further, we explore their role and clinical relevance in the context of cancer and describe how these cells may be used for the development of novel immunotherapeutic options to benefit patients with cancer with MHC class II-positive tumors.

Keywords:  Immunotherapy; T cell

DOI:  https://doi.org/10.1136/jitc-2025-013461
Oncol Res. 2025 ;33(12): 3657-3678

Mast Cells in the Solid Tumor Microenvironment: Multiple Roles and Targeted Therapeutic Potential.

Chenglu Lu, Huiting Zhang, Ujjal K Bhawal, Lei Wang, Jingwu Li, Pangzhou Chen, Lewei Zhu.

  The tumor microenvironment (TME) is a complex network composed of non-tumor cells, extracellular matrix, blood vessels, and various molecular signals that surround and profoundly influence tumor progression. As one of the key immune effector cells within the TME, mast cells (MCs) exhibit functional complexity, and their specific roles remain widely debated. Depending on the cancer type, spatial distribution, and interactions with other TME components, MCs can demonstrate dual regulatory capabilities-either promoting or inhibiting tumor growth. This characteristic has made them an important focus in current tumor immunology research. This review aims to systematically review the current understanding of MCs in the TME, with emphasis on their characteristics and functional differences across various tumor types, pathological status, and species. In recent years, advances in the understanding of MC markers, activation mechanisms, and biological functions have made targeting specific MC subsets an emerging therapeutic strategy. By comprehensively examining the origin, activation mechanisms, cellular interactions, and therapeutic regulation of MCs, this review provides new perspectives and a basis for future directions in tumor research and treatment.

Keywords:  Tumor microenvironment; cell communication; immunomodulatory; mast cell; mast cell activation; targeted therapy

DOI:  https://doi.org/10.32604/or.2025.069703
Mechanobiol Med. 2026 Mar;4(1): 100165

Mechano-regulation of cancer cell memory in tumor progression and therapy.

Yunjia Qu, Jiaxin Cui, Zhuohang Wu, Peixiang He, Fan Wei, Tianze Guo, Yixuan Huang, Xi Yu, Mishel Tsoy, Kunshu Liu, Ziyue Zhu, Yiming Zhang, Yingxiao Wang, Longwei Liu.

Cancer cell memory, the ability to retain responses to prior environmental stimuli, has emerged as a key driver of tumor progression, therapeutic resistance, and immune evasion. Mechanical cues within the tumor microenvironment (TME), including matrix stiffness, viscoelasticity, and compressive stress, are increasingly recognized as critical regulators of such memory. These biophysical inputs not only influence immediate cellular behavior but also induce long-lasting transcriptional, epigenetic, and phenotypic changes that sustain cancer cell aggressive traits. In this review, we specifically highlight mechanobiology in shaping cancer cell memory. We summarize how extracellular matrix (ECM) composition and remodeling encodes mechanical inputs into stable gene expression programs that promote tumor progression, and highlight how mechano-regulated plasticity, membrane tension, chromatin remodeling, and epigenetic changes govern self-renewal, differentiation, and drug and immune resistance, underscoring how physical suppression contributes to chemo-, radio-, and targeted therapies failure. We further discuss emerging mechano-targeted strategies, including ECM-degrading agents, sonogenetic engineered cells, and stiffness-responsive nanoparticles, that seek to rewire cancer cell memory and improve treatment outcomes.

DOI: https://doi.org/10.1016/j.mbm.2025.100165
Front Immunol. 2025 ;16 1700483

Sirtuins and tumor immunity: mechanistic insights, immunotherapy prospects, and therapeutic horizons.

Jinning Gu, Shanshan Liu, Wen Xiao, Wei Qu.

  Sirtuins (SIRTs), a family of NAD+-dependent enzymes, exhibit complex and sometimes opposing functions in cancer biology. These enzymes can function as tumor suppressors or promoters, depending on the cellular context, tumor type, and metabolic state. This review provides a mechanistic overview of SIRT isoform regulation of key oncogenic processes, including proliferation, metastasis, metabolic reprogramming, and chemotherapy resistance. Special emphasis is given to their immunomodulatory roles within the tumor microenvironment (TME), where SIRTs influence T cell differentiation, immune checkpoint expression, macrophage polarization, and natural killer cell function. SIRT-driven pathways, such as the nicotinamide phosphoribosyltransferase (NAMPT)-SIRT1-programmed Cell Death Ligand 1 (PD-L1) axis, SIRT6-induced regulatory T cell (Treg) formation, and SIRT2-driven T cell activation, are examined for their effects on immune escape or enhancement and their impact on immunotherapy responses. The review also explores how SIRTs contribute to adaptive mechanisms underlying chemoresistance, including autophagy, epithelial-mesenchymal transition (EMT), redox balance, and mitochondrial protection. The therapeutic landscape of targeting SIRTs is assessed, with discussion of isoform-selective modulators, combination strategies with checkpoint blockade, and challenges in leveraging their context-dependent activities. SIRTs are established as crucial regulators of cancer immunity and therapy, suggesting novel directions for precision oncology. However, given their isoform- and context-dependent duality across tumor types, the clinical translation of SIRT modulators requires careful mechanistic stratification and biomarker-guided patient selection.

Keywords:  chemoresistance; immune escape; immunotherapy; oncogenic processes; sirtuins

DOI:  https://doi.org/10.3389/fimmu.2025.1700483
Signal Transduct Target Ther. 2025 Dec 26. 10(1): 420

Inhibin beta A drives colorectal cancer progression through macrophage M2 polarization and mitochondria-dependent ferroptosis suppression.

Wentao Li, Lin Liang, Siyi Liu, Jingqiong Tang, Shuangyan Ou, Zhijun Yuan, Yanhong Zhou, Xia Yuan.

Colorectal cancer (CRC) is a prevalent malignant tumor, and its pathogenesis has not yet been fully elucidated. The tumor microenvironment (TME) and ferroptosis in cancer cells are key drivers of tumor progression and metastasis. This research revealed that elevated INHBA expression in CRC tissues correlates with unfavorable clinical outcomes. In vitro and in vivo studies demonstrated that elevated INHBA enhances CRC cellular growth, migration, and invasion, whereas INHBA knockdown inhibits these malignant biological behaviors. Further investigation revealed that INHBA drives malignancy by reprogramming tumor-associated macrophages (TAMs) toward the M2 phenotype in the TME and by inhibiting mitochondrial-dependent ferroptosis in CRC cells. Mechanistically, INHBA upregulates SLC25A10 to activate the succinate/SUCNR1 axis, thus facilitating M2-like TAM polarization. It also activates the mitochondrial glutathione (mtGSH)/glutathione peroxidase 4 (GPX4) pathway to suppress mitochondria-dependent ferroptosis in CRC cells. Additionally, INHBA acts as a scaffold protein to inhibit TRIM21-mediated ubiquitination and degradation of SLC25A10, thereby stabilizing the SLC25A10 protein. In summary, INHBA drives tumor progression by remodeling the immune microenvironment and antagonizing ferroptosis in CRC cells, providing a theoretical basis for developing INHBA-targeted inhibitors or combined immunoferroptosis therapeutic strategies. Mechanisms of INHBA in colorectal cancer In colorectal cancer, INHBA is upregulated. Acting as a scaffold protein, INHBA inhibits the K48-linked ubiquitination and degradation of the mitochondrial protein SLC25A10, mediated by the E3 ubiquitin ligase TRIM21. This inhibition leads to the upregulation of SLC25A10 expression. The upregulated SLC25A10 facilitates the transport of succinate from the mitochondrial matrix to the cytoplasm and further secretes it outside the tumor cells. The secreted succinate binds to SUCNR1 on macrophages, activating the succinate/SUCNR1 axis, which in turn promotes the M2 polarization of tumor-associated macrophages (TAMs). Meanwhile, SLC25A10, as one of the key mitochondrial glutathione (mtGSH) transporters embedded in the mitochondrial inner membrane, promotes the transport of glutathione (GSH) synthesized in the cytoplasm into the mitochondria. This process activates the mitochondrial GSH-GPX4 axis, thereby inhibiting mitochondrial ferroptosis. Through these two mechanisms, INHBA ultimately promotes the malignant progression of colorectal cancer.

DOI: https://doi.org/10.1038/s41392-025-02518-y
Tomography. 2025 Dec 17. pii: 143. [Epub ahead of print]11(12):

Cancer-Associated Fibroblasts: Clinical Applications in Imaging and Therapy.

Neda Nilforoushan, Ashkan Khavaran, Maierdan Palihati, Yashvi Patel, Anna O Giarratana, Jeeban Paul Das, Kathleen M Capaccione.

  Cancer-associated fibroblasts (CAFs) are an abundant and diverse cell population within tumor microenvironments of solid tumors. Multiple subtypes of CAFs, defined by molecular and functional markers, have been described in the literature. CAFs contribute to tumor progression by remodeling the extracellular matrix, promoting immune evasion, and supporting angiogenesis and metastasis. Fibroblast activation protein (FAP) is a transmembrane serine protease minimally expressed in normal adult tissues but significantly upregulated in certain subtypes of CAFs across many solid tumors. High levels of FAP have been associated with poor prognosis in various cancers. FAP has increasingly emerged as a promising target for both imaging and therapy. Multiple FAP-targeting strategies, such as small molecules, monoclonal antibodies, drug conjugates, and radiolabeled ligands, are currently being investigated in preclinical and early clinical settings. This review provides a clinically focused overview of CAFs in the tumor microenvironment, highlighting key fibroblast markers, their associations with prognosis across various tumor types, and their utility in radiologic imaging and targeted therapy. We also discuss the potential of non-FAP fibroblast targeting molecules and the clinical rationale for more selective, subtype-specific strategies. By examining fibroblast biology through a radiologist's lens, we aim to explore the evolving role of stromal targeting in imaging and the treatment of solid tumors.

Keywords:  cancer associated fibroblasts (CAFs); fibroblast activation protein (FAP); heterogeneity; imaging biomarkers; radioligand therapy; stromal targeting; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/tomography11120143
Oncoimmunology. 2026 Dec 31. 15(1): 2604877

IL-37/IL-1R8 axis: a novel major mechanism of control at the interface between tumor and immune cells.

Nadine Landolina, Francesca Romana Mariotti, Enrico Munari, Nicola Tumino, Paola Vacca, Bruno Azzarone, Lorenzo Moretta, Enrico Maggi.

  Interleukin (IL)-37 is one of the "youngest" IL-1 family members and one of the few molecules exerting anti-inflammatory activity. Upon inflammasome activation, the cytokine precursor is converted into its mature form, which acts intracellularly as a nuclear transcription factor, impairing the production of pro-inflammatory cytokines, and extracellularly by forming the IL-37/IL-18Rα/IL-1R8 complex, favoring IL-1R8 inhibitory signaling with immunosuppressive function. IL-1R8, which is mostly expressed in a number of cell types, negatively regulates both IL-1R/TLR signaling, blocking the NF-kB/JNK pathway and the production of pro-inflammatory cytokines. Owing to its ability to inhibit both innate and adaptive immunity, IL-37 has been reported to control inflammation in many chronic disorders, including cancer. IL-37 impairs the proliferation and migration of tumor cells, mediates anti-angiogenetic mechanisms, and favors immunoregulation in the tumor microenvironment (TME). This review aims to provide a current overview of IL-37 genetic and biological features and of its active interaction with IL-1R8, inducing anti-inflammatory effects on the immune system and affecting cancer cell dynamics in the TME. Moreover, it analyzes the rare pro-tumoral effects of IL-37 in some tumors and discusses their possible mechanisms. It concludes that, due to its strong anti-inflammatory property, IL-37 can be considered a potential regulator in the pathogenesis of a variety of cancers, slowing tumor progression through multiple pathways and providing valuable information for tumor immune target therapy.

Keywords:  IL-1R8; IL-37; immune cells; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2025.2604877
Comput Struct Biotechnol J. 2025 ;27 5537-5548

Immune and non-immune cell fencing of tumor cells is a widespread and functionally relevant spatial pattern in solid cancers.

Giuseppe Giuliani, Dhruv Chavan, Rushil Gaddam, William C Stewart, Zihai Li, Ciriyam Jayaprakash, Jayajit Das.

  Solid tumors are characterized by a spatially heterogeneous mixture of cancer cells, immune cells and other non-tumor cells. Recent characterization of the heterogeneity at the single cell level has revealed spatial patterns of different cell types often lacking a simple geometric structure associated with cancer progression. Here we investigated the occurrence of physical "fencing" of tumor cells by specific immune and non-immune phenotypes in the tumor microenvironment (TME) and the association of these clusters to cancer progression in a wide range of solid tumors formed in different organs. We analyzed published datasets providing patient tumor progression data coupled with imaging mass cytometry (IMC) data obtained from tumor tissues to characterize the presence of fencing clusters of various cell types and their association with differing patient outcomes. The six datasets spanned patients with triple-negative breast cancer (279 patients), lung cancer (416 patients), melanoma (30 patients), colorectal cancer (9 patients), glioma (185 patients), and head and neck cancer (139 patients). Devising and employing simple mechanistic and stochastic spatially-resolved computational models we examine two potential mechanistic hypotheses regarding the pro- and anti-tumor roles of a fencing cluster via physical blocking and chemokine gradient in the local environment, respectively. The fencing structures formed by non-tumor cells in the TME can be important for connecting microscopic cellular patterns to tumor progression and treatment responsiveness to immunotherapy in solid cancers.

Keywords:  Multi-cancer analysis; Solid cancers; Spatial mechanisms

DOI:  https://doi.org/10.1016/j.csbj.2025.11.062
Tissue Cell. 2025 Dec 16. pii: S0040-8166(25)00561-0. [Epub ahead of print]99 103279

The dual role of autophagy in breast cancer stemness and treatment resistance.

Anu Jayanthi Panicker, Kirti S Prabhu, Ummu Habeeba, Zahwa Mariyam, Affan Asim, Sarada Prasad Dakua, Shahab Uddin.

  Autophagy is a fundamental, highly conserved cellular process with a complex dual role in breast cancer progression and therapy resistance. Initially, autophagy functions as a tumor suppressor by maintaining genomic stability through clearance of damaged organelles and reducing oxidative stress, preventing tumor initiation. In established tumors, autophagy supports cancer cell survival under metabolic stress, sustains cancer stem cell stemness, and facilitates adaptation to hypoxia and nutrient deprivation in the tumor microenvironment. This pro-survival role enhances tumor growth, metastasis, and resistance to chemotherapy, radiotherapy, and targeted therapies. Autophagy extensively interacts with key signaling pathways governing cancer stem cell renewal and immune evasion, underscoring its multifaceted impact on tumor biology. Given its pivotal role, autophagy modulation via established inhibitors such as chloroquine alone and in combination with several other novel agents are under clinical investigation to investigate if its action that could be used to overcome therapy resistance and improve patient outcomes in breast cancer.

Keywords:  Autophagy; Breast cancer; Cancer stem cells; Chemotherapy

DOI:  https://doi.org/10.1016/j.tice.2025.103279
Biochim Biophys Acta Rev Cancer. 2025 Nov;pii: S0304-419X(25)00229-X. [Epub ahead of print]1880(6): 189487

Immune archetypes TIME classification system for nasopharyngeal carcinoma: A new direction for precision immunotherapy.

Fei Lu, Xueqi Bai, Zihan Lv, Wenling Zhang.

  In the complex tumor immune microenvironment (TIME), tumor cells are typically surrounded by host immune components that can either suppress or promote tumor progression. The stromal compartment usually responds to tumor cells through inflammatory processes, often reflecting a single immune state or class. This pattern is also observed in the tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC). However, recent advances in single-cell profiling have revealed that multiple distinct immune states can coexist around NPC tissues. In this review, we delineate and classify the immune "archetypes" of TMEs in NPC-defined as cellular assemblages and gene expression profiles that are characteristic and recurrent at the bulk tumor level. We further summarize studies suggesting that NPC TMEs can be broadly categorized into 11 major immune archetypes. Considering their potential evolutionary origins and functional roles, these archetypes appear to be associated with specific vulnerabilities within the TME, which may be exploited as therapeutic targets. Such insights may provide novel strategies for NPC treatment, thereby enhancing patient outcomes and improving prognosis.

Keywords:  Classification system; Immune archetypes; Immunotherapy; Nasopharyngeal carcinoma; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189487
Cytokine Growth Factor Rev. 2025 Dec 15. pii: S1359-6101(25)00166-2. [Epub ahead of print]87 102-112

Interferons as therapeutic orchestrators of cancer stem cell plasticity and therapy response.

Deepakshi Kasat, Sophia Hidalgo, Lu Wang, Jack D Bui, Magalie Dosset.

  Cancer stem cells (CSCs) represent a small but critical subset of tumor cells characterized by their inherent self-renewal ability, differentiation potential, and resistance to cancer therapies. Their capacity to reversibly transition between a stem-like and differentiated state, together with their ability to enter into quiescence, are key determinants of their contribution to tumor initiation, tumor progression, metastasis, and cancer recurrence. Among the various factors in the tumor microenvironment, increasing evidence suggests that interferons (IFNs) are key extrinsic modulators of CSC fate. Although type I (IFN-α/β) and type II (IFN-γ) IFNs have long been recognized for their antitumor properties, recent studies indicate that IFN-signaling may also facilitate CSC induction and maintenance. In this review, we summarize and critically assess our current understanding of the complex roles of IFNs in governing CSC survival, plasticity, and immunogenicity. We discuss how IFN-signaling thresholds, signaling duration, and intrinsic CSC regulatory networks determine whether IFNs suppress CSCs or instead reinforce stemness. By bridging mechanistic insights with therapeutic potential and clinical outcomes, we highlight emerging opportunities to exploit IFN pathways for improved biomarkers and therapeutic strategies to overcome CSC-driven resistance.

Keywords:  Biomarkers; Cancer stem cells; Cancer therapy; IFN signaling; Immune checkpoint therapy; Tumor resistance

DOI:  https://doi.org/10.1016/j.cytogfr.2025.12.008
J Cancer. 2026 ;17(1): 157-176

Macrophages in Colorectal Cancer: from Normal Mucosa to Distant Metastasis: Beyond the M1/M2 Paradigm.

Sergii Pavlov, Esraa Ali, Filip Ambrozkiewicz, Wenjing Ye, Marie Rajtmajerová, Václav Liška, Kari Hemminki, Andriy Trailin.

  Colorectal cancer (CRC) is the third most common malignancy and leading cause of mortality worldwide. Tumor microenvironment (TME) strongly influences CRC growth, immune evasion, and metastasis. Among various immune cells, tumor-associated macrophages (TAMs) act as key regulators of cancer progression. Although traditionally classified as M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor), single-cell RNA sequencing and spatial transcriptomics have revealed that macrophage phenotypes exist along a continuum, challenging the classic dichotomy. This review investigates macrophages throughout CRC development, from normal mucosa to adenoma, primary tumor, and liver metastasis. Early adenomas feature M1-like macrophages that drive local inflammation, whereas advanced adenomas and invasive CRC comprise M2-like macrophages promoting angiogenesis, extracellular matrix remodeling, and immunosuppression. TAMs are crucial in CRC metastasis, particularly to the liver. M2-polarized Kupffer cells express CD206 and CD163, secrete hepatocyte growth factor, and activate PI3K/AKT signaling, thus aiding extravasation, survival, and proliferation of metastatic cells. They also foster lymphangiogenesis and immunosuppression through release of IL-10 and TGF-β. CRC's consensus molecular subtype (CMS) impacts the profile of TAMs: CMS1 (microsatellite instability-high) tumors typically harbor an anti-tumor M1 macrophages, while CMS4 (mesenchymal) tumors are enriched in M2-like TAMs, which facilitate stromal remodeling and angiogenesis, ultimately contributing to a poor prognosis. Spatial distribution also matters. Abundant M1 macrophages at the invasive margin correlate with better outcomes, whereas M2 macrophages in tumor centers and metastatic sites drive disease progression. Some CD206+ macrophages, however, support vascular normalization, which can limit metastasis. These findings underscore the complexity of TAMs in CRC and highlight the necessity of multi-marker phenotyping. Given the limitations of the M1/M2 paradigm, advanced techniques such as spatial transcriptomics and single-cell RNA sequencing offer novel insights into TAM heterogeneity. Future therapeutic strategies targeting TAMs, including metabolic reprogramming, epigenetic modulators, and immune checkpoint inhibitors, hold promise for improving CRC patient outcomes by shifting the balance toward an anti-tumor immune response.

Keywords:  M1/M2 markers; adenoma-colorectal cancer-liver metastasis sequence; colorectal cancer; normal mucosa; prognostic significance.; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.7150/jca.126772
Bioessays. 2026 Jan;48(1): e70101

Using Mathematical Modeling of Tumor Metabolism to Predict the Magnitude, Composition, and Hypoxic Interactions of Microenvironment Acidosis.

Alzbeta Hulikova, Pawel Swietach.

In well-perfused tissues, interstitial composition resembles capillary plasma. Solid tumors break this norm because cancer cell proliferation outpaces vascular expansion, leading to a diffusion-limited tumor microenvironment (TME) that is notably depleted of oxygen and enriched in acids. The magnitude of tumor acidosis; its chemical composition in terms of [CO2] and [HCO3 -] (components of the major extracellular buffer); and its relationship with hypoxia are not intuitive to predict but important to know for designing experiments and contextualising results. We address these timely questions using mathematical models of a monolayer, spheroid, and poorly-perfused tissue. Our simulations suggest a physiologically realistic TME pH range of 6.7-7.4, reveal a prominence of hypercapnia, and indicate varying levels of HCO3 - depletion or accumulation arising from fermentation and respiration, respectively. The trajectories of tumor hypoxia and acidosis depend on the balance between aerobic and anaerobic pathways, with important consequences on hypoxic signaling where many responses are pH-sensitive.

DOI: https://doi.org/10.1002/bies.70101
Mol Cancer Ther. 2025 Dec 22.

CHS-114: an afucosylated anti-CCR8 monoclonal antibody that selectively depletes intratumoral Treg cells and induces antitumor immune responses.

Xiaoguang Wang, Varun N Kapoor, Daniel J Chin, Scott L Klakamp, Federico Baruffaldi, James F Mohan, Robert Haines, Austin Dulak, Marisella Panduro, Yue Ren, Ricard Masia, Jonathan A Hill, Theresa M LaVallee, Narendiran Rajasekaran.

Intratumoral T regulatory cells (Tregs) promote an immunosuppressive tumor microenvironment and are frequently associated with a lack of response to immunotherapy. Selective targeting of intratumoral Tregs while sparing broader Tregs and effector T cell populations is an attractive strategy to enhance antitumor immune responses. CCR8 is a G protein-coupled receptor (GPCR) that is predominantly upregulated on tumor resident Tregs in a range of human solid tumors making it a promising target for their selective depletion. In preclinical studies using the mouse tumor models, anti-mouse CCR8 antibody treatment resulted in depletion of CCR8+ intratumoral Tregs, significant antitumor activity and enhanced survival in combination with anti-PD-1. CHS-114 is a highly selective, afucosylated human anti-CCR8 monoclonal antibody that is being developed as a cancer immunotherapy. CHS-114 selectively binds human CCR8 and potently kills CCR8 expressing cells by inducing antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Ex vivo studies evaluating human dissociated tumor cells (DTCs) demonstrated the selectivity of CHS-114 in depleting intratumoral Tregs while sparing CCR8 negative Tregs and effector T cells. Treatment of tumor bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643, NCT06657144).

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0367
Oncol Res. 2025 ;33(12): 3789-3800

Unraveling Immunotherapy Resistance in Solid Tumors: Decoding Mechanisms and Charting Future Therapeutic Landscapes.

Huan Wang, Jindong Xie, Na Li, Qianwen Liu, Wenqi Song, Wenkuan Chen, Cheng Peng, Hailin Tang.

  Solid tumors comprise the majority of the global cancer burden, with their incidence and associated mortality posing considerable challenges to public health systems. With population growth and aging, the burden of these tumors is anticipated to increase further in the coming decades. The progression of solid tumors depends on dynamic interactions between malignantly transformed cells and the tumor microenvironment (TME). Immune checkpoint inhibitor therapy improves T cell-mediated antitumor activity by suppressing regulatory pathways, such as programmed cell death protein 1/programmed death-ligand 1. Nonetheless, its widespread application is constrained by drug resistance. In this comprehensive review, we elucidate the latest advances in understanding the mechanisms underlying drug resistance, explore pioneering approaches, such as combination therapeutic regimens and nanoscale drug delivery platforms, and propose future avenues for research. These include investigating the intricacies of drug resistance pathways, refining combination therapy strategies, and modulating the TME, along with other key areas.

Keywords:  ICI; Solid tumor; TME; drug resistance; immune checkpoint inhibitor; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2025.067592