Lactylation‐Driven NUPR1 Promotes Immunosuppression of Tumor‐Infiltrating Macrophages in Hepatocellular Carcinoma DOI Creative Commons

Jia-Liang Cai,

Peiling Zhang,

Yufan Cai

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

While checkpoint immunotherapy effectively mobilizes T-cell responses against tumors, its success in hepatocellular carcinoma (HCC) is frequently undermined by immunosuppressive myeloid cells within the tumor microenvironment. This study investigates role of nuclear protein 1 (NUPR1), a gene prominently expressed tumor-associated macrophages (TAMs), mediating this suppression and influencing outcomes. Through comprehensive analysis single-cell RNA sequencing (scRNA-seq) datasets functional assays vitro vivo, NUPR1 identified as critical regulator TAMs. The upregulation associated with enhanced M2 macrophage polarization increased expression immune checkpoints PD-L1 SIRPA, resulting CD8+ T cell exhaustion diminished response to immunotherapy. Mechanistically, inhibits ERK JNK signaling pathways, thereby creating an milieu conducive progression. Additionally, tumor-derived lactate shown upregulate via histone lactylation, perpetuating feedback loop that intensifies suppression. Pharmacological targeting reverses polarization, curtails growth, augments efficacy PD-1 blockade preclinical models, positioning both potential biomarker for responsiveness therapeutic target boost HCC.

Language: Английский

Targeting of TAMs: can we be more clever than cancer cells? DOI Creative Commons
Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1376 - 1409

Published: Nov. 8, 2024

АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes death, reduced quality life disability worldwide. Principal progress in development new anticancer therapies, improving efficiency immunotherapeutic tools, personification conventional therapies needs to consider cancer-specific patient-specific programming innate immunity. Intratumoral TAMs their precursors, resident macrophages monocytes, are principal regulators tumor progression therapy resistance. Our review summarizes accumulated evidence for subpopulations number biomarkers, indicating predictive value clinical parameters carcinogenesis resistance, with a focus on solid cancers non-infectious etiology. We present state-of-the-art knowledge about tumor-supporting functions at all stages highlight recently identified by single-cell spatial analytical methods, that discriminate between tumor-promoting tumor-inhibiting TAMs, where both subtypes express combination prototype M1 M2 genes. focuses novel mechanisms involved crosstalk among epigenetic, signaling, transcriptional metabolic pathways TAMs. Particular attention has been given link cell metabolism epigenetic histone lactylation, which can be responsible unlimited protumoral Finally, we explain how interfere currently used therapeutics summarize most advanced data from trials, divide into four categories: inhibition TAM survival differentiation, monocyte/TAM recruitment tumors, functional reprogramming genetic enhancement macrophages.

Language: Английский

Citations

18
CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial DOI
Kim A. Reiss, Mathew G. Angelos,

E. Claire Dees

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

Citations

6
Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma DOI Creative Commons

Qinlei Wang,

Zhaowei Sun,

Jingyun Guo

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: 617, P. 217596 - 217596

Published: March 12, 2025

M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators intercellular communication. However, relationship between cell-induced PNI cholangiocarcinoma remains unexplored. study, we utilized multiplex immunofluorescence transcriptomic sequencing demonstrate upregulation LINC01812 tissues its positive correlation macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, mass spectrometry analysis demonstrated that can internalize exosomal promote phenotype cells. Additionally, Transwell vitro cocultures dorsal root ganglia confirmed significantly enhances nerve infiltration cells via macrophages. The findings study indicate containing derived from induce polarization facilitate infiltration, thereby providing new potential therapeutic targets for managing cholangiocarcinoma.

Language: Английский

Citations

2
Targeting conserved TIM3 + VISTA + tumor-associated macrophages overcomes resistance to cancer immunotherapy DOI Creative Commons
Isaure Vanmeerbeek, Stefan Naulaerts, Jenny Sprooten

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(29)

Published: July 19, 2024

Despite the success of immunotherapy, overcoming immunoresistance in cancer remains challenging. We identified a unique niche tumor-associated macrophages (TAMs), coexpressing T cell immunoglobulin and mucin domain–containing 3 (TIM3) V-domain suppressor activation (VISTA), that dominated human mouse tumors resistant to most currently used immunotherapies. TIM3 + VISTA TAMs were sustained by IL-4–enriching with low (neo)antigenic cell–depleted features. showed an anti-inflammatory protumorigenic phenotype coupled inability sense type I interferon (IFN). This was established cells succumbing immunogenic death (ICD). Dying not only triggered autocrine IFNs but also exposed HMGB1/VISTA engaged TIM3/VISTA on suppress paracrine IFN-responses. Accordingly, blockade synergized paclitaxel, ICD-inducing chemotherapy, repolarize proinflammatory killed via tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) signaling. propose targeting overcome immunoresistant tumors.

Language: Английский

Citations

15
Lipid-associated macrophages between aggravation and alleviation of metabolic diseases DOI Creative Commons
Ruonan Xu, Nemanja Vujić, Valentina Bianco

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(11), P. 981 - 995

Published: May 4, 2024

Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals obesity, liver lesions steatosis and steatohepatitis, the intestinal lamina propria. LAMs can also emerge metabolically demanding microenvironment certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, self-renewal, and, ultimately, their acute chronic functional impact on development diseases. Further studies need clarify whether under which circumstances drive progression or resolution how phenotype be modulated ameliorate disorders.

Language: Английский

Citations

13
Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication DOI Creative Commons
Hua Wang, Tao Wang, Shuxiang Yan

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Nov. 30, 2024

In the realm of cancer research, tumor microenvironment (TME) plays a crucial role in initiation and progression, shaped by complex interactions between cells surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted various cellular constituents within TME, including immune cells, cancer-associated fibroblasts, themselves. These cytokines facilitate intricate communication networks that significantly influence initiation, metastasis, suppression. Pyroptosis contributes to TME remodeling promoting release pro-inflammatory sustaining chronic inflammation, impacting processes such escape angiogenesis. However, challenges remain due interplay among cytokines, pyroptosis, along with dual effects pyroptosis on progression therapy-related complications like cytokine syndrome. Unraveling these complexities could strategies balance inflammatory responses while minimizing tissue damage during therapy. This review delves into crosstalk elucidating their contribution metastasis. By synthesizing emerging therapeutic targets innovative technologies concerning this aims provide novel insights enhance treatment outcomes for patients.

Language: Английский

Citations

12
Macrophage diversity in human cancers: New insight provided by single-cell resolution and spatial context DOI Creative Commons
Militsa Rakina, Irina Larionova, Julia Kzhyshkowska

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(7), P. e28332 - e28332

Published: March 22, 2024

M1/M2 paradigm of macrophage plasticity has existed for decades. Now it becomes clear that this dichotomy doesn't adequately reflect the diversity phenotypes in tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a major population innate immune cells TME promotes cell proliferation, angiogenesis and lymphangiogenesis, invasion metastatic niche formation, as well response to anti-tumor therapy. However, fundamental restriction therapeutic TAM targeting is limited knowledge about specific states distinct human cancer types. Here we summarized results most recent studies use advanced technologies (e.g. single-cell RNA sequencing spatial transcriptomics) allowing decipher novel functional subsets TAMs numerous cancers. The transcriptomic profiles these their clinical significance were described. We emphasized characteristics subpopulations – TREM2+, SPP1+, MARCO+, FOLR2+, SIGLEC1+, APOC1+, C1QC+, others, which have been extensively characterized several cancers, associated with prognosis. Spatial transcriptomics defined interactions between other types, especially fibroblasts, tumors. methods also applied identify markers immunotherapy response, expressed by or macrophage-abundant regions. highlighted perspectives techniques utilize single resolution investigating new ligand-receptor effective based on TAM-targeting.

Language: Английский

Citations

9
Single-cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche DOI Creative Commons

Yasmin Henlon,

Kavita Panir,

Iona McIntyre

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(38)

Published: Sept. 10, 2024

Endometriosis negatively impacts the health-related quality of life 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role pathophysiology endometriosis and represent promising therapeutic target. In current study, we revealed full transcriptomic complexity endometriosis-associated macrophage subpopulations using single-cell analyses preclinical mouse model experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression Folr2 , Mrc1 Gas6, Ccl8+ ) promoted Col1a1 Tgfb1 human endometrial stromal cells increased angiogenic meshes umbilical vein endothelial cells, ii) scar-associated ( Mmp12, Cd9, Spp1, Trem2 +) exhibited phenotype associated with fibrosis matrix remodeling. also described population proresolving large peritoneal align lipid-associated Apoe, Saa3, Pid1 concomitant altered lipid metabolism cholesterol efflux. Gain function experiments an Apoe mimetic resulted decreased lesion size fibrosis, modification model. Using cross-species analysis datasets, determined concordance subpopulations, identifying similarities differences phenotypes. Ultimately, envisage these findings will inform design use specific macrophage-targeted therapies open broad avenues treatment

Language: Английский

Citations

9
Macrophage Polarization: Learning to Manage It 3.0 DOI Open Access
Nadia Lampiasi

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 311 - 311

Published: Jan. 1, 2025

Macrophages are cells of the innate immune system with very peculiar characteristics, so plastic that they respond rapidly to environmental changes by assuming different and sometimes contrasting functions, such as initiating a physiological inflammatory response or interrupting it repairing damaged tissues [...]

Language: Английский

Citations

1
Engineering CAR‐T Therapeutics for Enhanced Solid Tumor Targeting DOI Creative Commons
Danqing Zhu, Wonjoon Kim, Hyunjin Lee

et al.

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Cancer immunotherapy, specifically Chimeric Antigen Receptor (CAR)‐T cell therapy, represents a significant breakthrough in treating cancers. Despite its success hematological cancers, CAR‐T exhibits limited efficacy solid tumors, which account for more than 90% of all Solid tumors commonly present unique challenges, including antigen heterogeneity and complex tumor microenvironment (TME). To address these, efforts are being made through improvements CAR design the development advanced validation platforms. While is limited, some types, such as neuroblastoma gastrointestinal have shown responsiveness to therapy recent clinical trials. In this review, it first examined both experimental computational strategies, protein engineering coupled with machine learning, developed enhance T specificity. The challenges methods associated delivery vivo reprogramming discussed. It also explored advancements engineered organoid systems, emerging high‐fidelity vitro models that closely mimic human TME serve platform discovery. Collectively, these innovative strategies offer potential revolutionize next generation ultimately paving way effective treatments tumors.

Language: Английский

Citations

1