Tumor Microenvironment Research Articles

Implantable Biomaterials for Cancer Immunotherapies

AbstractCancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to target and eliminate tumor cells. Implantable biomaterials, such as hydrogels, sponges, scaffolds, implantable microdevice platforms, and macrobeads, offer localized and sustained release of immunomodulatory agents, improving the delivery of treatments such as immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies like CAR‐T cells. This review examines the emerging role of these biomaterials in modulating the tumor microenvironment, enhancing immune cell recruitment, and reducing systemic side effects, positioning them as significant tools for treating solid tumors. Recent advances in material engineering are also discussed, including the integration of bioactive molecules and real‐time therapeutic adjustments based on patient‐specific immune responses, which offer new potential in personalized cancer treatments. However, challenges such as biocompatibility, high production costs, variability in patient response, and the necessity of surgical manipulations remain key obstacles. Nonetheless, ongoing research and technological advancements are steadily addressing these issues, paving the way for more effective and accessible cancer immunotherapies. Overall, this review highlights the promise of implantable biomaterials overcoming the current limitations of cancer immunotherapy and expanding the scope of effective, targeted cancer treatments.

Treatment of cancer-associated fibroblast-like cells with celecoxib enhances the anti-cancer T helper 1/Treg responses in breast cancer.

Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10µM of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (α-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-β1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-ɣ, IL-10, IL-4, TGF-β1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of α-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFNγ expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-β1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.

Application of Immunotherapy in Brain Cancer Treatment

Brain cancer is a malignant tumor, characterized by abnormal growth of cells in the brain. The high mortality rate and poor prognosis of brain cancer make it become a notable cancer type. Statistics demonstrate that the incidence of brain cancer is still increasing, hence, studies on immunotherapy of brain cancer, one of the most common and vital therapies in treating cancer, becomes important. This review mainly introduces three kinds of immunotherapy, including vaccines, immune checkpoint inhibitors (ICIs) and Chimeric Antigen Receptor (CAR) T-cell therapy. Even though these treatments share similar basic mechanisms, taking advantage of host immune system, they are different in the way of evoking immune response. Both vaccines and CAR-T utilize the binding between pathogenic substance and immune cell, while the ICIs rely on the release of immune suppression. Most of the immunotherapeutic strategies have shown great efficiency, and the corresponding side effects also exist, which still need to be explored, like the inefficiency caused by the complex tumor microenvironment and the off-target issue risen by the scarcity of tumor-specific antigens. Therefore, novel combinations of different therapies and designs of research may be the new trends of the immunotherapy for brain cancer.

Framework Nucleic Acids: Innovative Tools for Cellular Sensing and Therapeutics.

As emerging biomaterials, framework nucleic acids (FNAs) have recently demonstrated great potential in the biomedical field due to their high programmability, biocompatibility, unique structural diversity, and precise molecular design capabilities. This review focuses on the applications of FNAs in cellular sensing and disease treatment. First, we systematically introduce the applications of FNAs in cellular sensing, including their precise recognition and response to the extracellular tumor microenvironment, cell membrane proteins, and intracellular biomarkers. Subsequently, we review the potential of FNAs in disease treatment, covering their applications and development in drug delivery, regulation of cell behavior, and immunomodulation. We also discuss the limitations and potential role of FNAs in personalized medicine, precision diagnostics, and advanced therapies. The broad application of FNAs is expected to drive significant breakthroughs in future biomedical technological innovations and clinical translation.

Photoacoustic Imaging of pH-Sensitive Optical Sensors in Biological Tissues

Photoacoustic imaging is an emerging biomedical imaging technique that enables non-invasive visualization of the optical absorption properties of biological tissues in vivo. Although numerous studies have used contrast agents to achieve high-contrast imaging in deep tissues, targeting specific areas remains a challenge when using agents that are continuously activated. Recent research has focused on developing triggered contrast agents that are selectively activated in target areas. This review delves into the use of pH-triggered contrast agents in photoacoustic imaging, which take advantage of the lower pH of the tumor microenvironment compared to normal tissues. The paper discusses the mechanisms of pH-triggered contrast agents that contribute to improving depth and contrast in photoacoustic tumor imaging. In addition, the integration of functionalities, such as photothermal therapy and drug delivery monitoring, into these agents demonstrates significant potential for biomedical applications.

Coupling Probiotics with CaO2 Nanoparticle-Loaded CoFeCe-LDH Nanosheets to Remodel the Tumor Microenvironment for Precise Chemodynamic Therapy.

Chemodynamic therapy (CDT) has become an emerging cancer treatment strategy with advantages of tumor-specificity, high selectivity, and low systemic toxicity. However, it usually suffers from low therapeutic efficacy. This is caused by low hydroxyl radical (·OH) yield arising because of the relatively high pH, overexpressed glutathione, and low H2O2 concentration in the tumor microenvironment (TME). Herein, a probiotic metabolism-initiated pH reduction and H2O2 supply-enhanced CDT strategy is reported to eradicate tumors by generating ·OH, in which Lactobacillus acidophilus is coupled with CoFeCe-layered double hydroxide nanosheets loaded with CaO2 nanoparticles (NPs) as a chemodynamic platform for high-efficiency CDT (CaO2/LDH@L. acidophilus). Owing to the hypoxia tropism of L. acidophilus, CaO2/LDH@L. acidophilus exhibits increased accumulation at tumor sites compared with the CaO2/LDH. The CaO2 NPs loaded on CoFeCe-LDH nanosheets are decomposed into H2O2 in the TME. L. acidophilus metabolite-induced pH reduction (<5.5) and CaO2-mediated in situ H2O2 generation synergistically boost ·OH generation activity of the CoFeCe-LDH nanosheets, effectively damaging cancer cells and ablating tumors with a tumor inhibition rate of 96.4%, 2.32-fold higher than that of CaO2/LDH. This work demonstrates that probiotics can function as a tumor-targeting platform to remodel the TME and amplify ROS generation for highly efficient and precise CDT.

Vascular smooth muscle cell plasticity in the tumor microenvironment.

Vascular smooth muscle cell plasticity in the tumor microenvironment.

Exploring the Role of Fibroblasts in Promoting Neuroblastoma Cell Migration and Invasion

Neuroblastoma, the most common pediatric extracranial solid tumor, arises from the malignant transformation of neural crest progenitors in the peripheral nervous system. Its clinical and genetic heterogeneity poses significant challenges, especially in high-risk patients with metastatic disease. Two plastic neuroblastoma cell phenotypes, adrenergic (ADR) and mesenchymal (MES), have been identified. Notably, MES neuroblastoma cells exhibit increased migration and chemoresistance. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment further promote tumor aggressiveness by enhancing cancer cell proliferation, extracellular matrix remodeling, angiogenesis and metastasis. This study explored the role of non-activated fibroblasts in ADR and MES neuroblastoma cell proliferation, migration and invasion in vitro and in vivo. Results showed that MES and ADR neuroblastoma cells influenced fibroblast activation into CAFs differently, with MES cells promoting a more invasive environment leading to tumor spread. These findings enhance our understanding of how ADR and MES phenotypes contribute to the formation of a pro-metastatic niche by activating fibroblasts in CAFs. This insight could inform new therapeutic strategies targeting the tumor microenvironment to prevent neuroblastoma metastasis.

PH-Responsive Persistent Luminescent Nanosystem with Sensitized NIR Imaging and Ratiometric Imaging Modes for Tumor Surgery Navigation.

Owing to autofluorescence-free feature, persistent luminescent (PersL) nanoparticles (PLNPs) become potential materials for tumor surgical navigation. However, it is still challenging to enhance PersL intensity, contrast ratio, and imaging stability so as to meet clinical demand and avoid missed detection of microlesions. Herein, integrating a tumor microenvironment (TME)-responsive strategy, sensitization enhancement, and internal-standard ratiometric method, a dual-mode PersL imaging strategy is proposed: After loading pH-responsive fluorescent molecule Rh-ADM on PLNPs ZnGa2O4:Cr3+,Mn2+ (ZGCM-Rh8), the fluorescence resonance energy transfer (FRET) pathways between Cr3+ and Rh-ADM, as well as Mn2+ and Rh-ADM, could sensitize the NIR PersL emitted by Cr3+ and quench the green PersL from Mn2+ at acidic TME, respectively. As a result, ZGCM-Rh8 is endowed with WLED (white light LED)-excited NIR imaging mode and UV-excited ratiometric imaging mode. Under WLED, ZGCM-Rh8 realizes 4.5-fold PersL enhancement and 97.9 as the maximum tumor contrast after precise control of Rh-ADM contents, helping with the preoperative diagnosis of deep lesions. Under UV, ZGCM-Rh8 conducts ratiometric PersL imaging steadily, and the "NIR/Vis" ratios at the tumor keep larger than 110, succeeding in detecting out a 1.5 mm small lesion and serving thorough surgical elimination of H22 ectopic intramuscular tumor in balb/c mice. To our knowledge, ZGCM-Rh8 is the first to realize pH-responsive PersL sensitization and apply ratiometric PersL imaging technology to surgical navigation.

Mild Magnetothermal Immunotherapy for Malignant Pleural Effusion.

Malignant pleural effusion (MPE) is one of the most difficult complications of cancer to cure, usually indicating poor prognosis in late-stage cancer patients. Due to the presence of a large number of tumor-associated immune cells with the tumor promoting phenotype in MPE and pleural tumors, current clinical therapy offers limited effectiveness. Here, a mild magnetothermal regulation strategy is proposed based on a magnetic nanocatlytic nanoplatform ZCMF@PEG-AF (ZCMF-AF)constructed by surface-modifying anti-F4/80 antibody (AF) on ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (ZCMF) to target and polarize tumor-associated macrophages. Under alternating magnetic field-induced hyperthermia (41-42°C), ZCMF-AF exhibits in situ nanocatalytic production of hydroxyl radicals via released iron ions under acidic cellular environment, which induces repolarization from the immunosuppressed M2 phenotype to the M1 phenotype. More importantly, the tumor cell damage induced by M1 macrophages and magnetic hyperthermia promote the maturation of dendritic cells, which subsequently awakens cytotoxic T lymphocytes to combat tumor cells. The integrated innate and adaptive immunity activations based on ZCMF-AF nano-immunomedicine through intrapleural administration elicit substantially regulated immune microenvironment of MPE and pleural tumors. Moreover, the interpleural magnetic nanoparticle-based immunotherapy effectively reduced the MPE volume and inhibited tumor growth in the pleural cavity, significantly prolonging the survival of the MPE-bearing mice.

Natural killer cells as promising candidates in Cancer therapeutics and related immune resistance in tumor microenvironment

Natural killer (NK) cells, as critical components of the innate immune system, have emerged as promising candidates in cancer therapy due to their ability to recognize and destroy tumor cells without prior sensitization. Their mechanisms of action, including perforin-granzyme release and antibody-dependent cellular cytotoxicity (ADCC), position them as versatile agents in cancer immunotherapy. Recent advancements, such as chimeric antigen receptor (CAR)-NK cells and cytokine-based stimulation, have demonstrated enhanced efficacy and reduced side effects compared to conventional immunotherapies. However, the immunosuppressive tumor microenvironment (TME) remains a significant obstacle, imposing challenges like immune checkpoint activation, cytokine suppression, and metabolic constraints that impair NK cell activity. This paper explores the therapeutic potential of NK cells, the challenges of immune resistance in the TME, and emerging strategies to enhance NK cell efficacy. Addressing these challenges is crucial for optimizing NK cell-based treatments and achieving durable responses in cancer patients.

Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits.

The tumor microenvironment (TME) is enriched with immunosuppressive factors that inhibit the recruitment and activation of dendritic cells (DCs), thereby reducing the efficacy of tumor immunotherapy. To address this challenge, we propose an innovative strategy involving the sequential administration of MCM magnetic nanoparticles carrying PROTAC drugs (MCM/ARV) and M-BMDCs in the TEM. This approach not only replenishes DCs in the TEM, but also increases antigen uptake through the attraction between the magnetic particles and promotes DC activation and antigen presentation, thus continuously enhancing the tumor immune cycle. MCM nanoparticles (magnetic nanoclusters coated with calcium-doped manganese carbonate) efficiently load the tumor-targeting drug PROTAC (ARV-825), enhancing its bioavailability, leading to specific degradation of BRD4 in tumor cells, and releasing a large number of tumor-associated antigens. These antigens were captured by MCM nanoparticles to construct magnetized tumor vaccines. Magnetic M-BMDCs introduced at the tumor site are attracted to these magnetized vaccines, resulting in a significant increase in antigen uptake and activation of DCs, significantly enhancing the tumor immune cycle. This co-administration strategy of magnetized vaccines and magnetized BMDCs provides a unique combination therapy for reversing immunosuppressive TEM and enhancing the efficacy of tumor immunotherapy.

CAR T Cell Nanosymbionts: Revealing the Boundless Potential of a New Dyad

Cancer treatment has traditionally focused on eliminating tumor cells but faces challenges such as resistance and toxicity. A promising direction involves targeting the tumor microenvironment using CAR T cell immunotherapy, which has shown potential for treating relapsed and refractory cancers but is limited by high costs, resistance, and toxicity, especially in solid tumors. The integration of nanotechnology into ICAM cell therapy, a concept we have named “CAR T nanosymbiosis”, offers new opportunities to overcome these challenges. Nanomaterials can enhance CAR T cell delivery, manufacturing, activity modulation, and targeting of the tumor microenvironment, providing better control and precision. This approach aims to improve the efficacy of CAR T cells against solid tumors, reduce associated toxicities, and ultimately enhance patient outcomes. Several studies have shown promising results, and developing this therapy further is essential for increasing its accessibility and effectiveness. Our “addition by subtraction model” synthesizes these multifaceted elements into a unified strategy to advance cancer treatment paradigms.

Microgels of N-Isopropylacrylamide Copolymerized with an Amphiphilic Acid for the Delivery of Doxorubicin

This study aims to design microgels that are thermo- and pH-sensitive for controlled doxorubicin (Dox) release in response to tumor microenvironment changes. N-isopropylacrylamide (NIPAAm) is widely used for thermoresponsive tumor-targeted drug delivery systems for the release of therapeutic payloads in response to temperature changes. Herein, a NIPAAm microgel (MP) that is responsive to temperature and pH was designed for the smart delivery of Dox. MP was made from NIPAAm, and polyethylene glycol methyl ether methacrylate (PEGMA) was copolymerized with 5%, 10%, or 15% mol of methacryloylamido hexanoic acid, (CAM5) an amphiphilic acid. We characterized the microgels using FTIR-ATR, DLS, and FESEM. The MP 10% CAM5 exhibited a particle size of 268 nm, with a transition temperature of 44 °C. MP had a drug loading capacity of 13% and entrapment efficiency of 87%. Nearly 100% of the Dox was released at pH 5 and 42 °C, compared to 30% at pH 7.4 and 37 °C. MP 10% CAM5 showed cytocompatibility in HeLa cells using the MTT assay. However, the cell viability assay showed that dox-MP was twice as effective as free Dox. Specifically, 3 μg/mL of free Dox resulted in 74% cell viability, while the same doses of Dox in NP reduced it to 35%. These results are promising for the future tumor-targeted delivery of antineoplastic-drugs, as they may reduce the side effects of Dox.

The pan-cancer landscape of aldo-keto reductase1B10 reveals that its expression is diminished in gastric cancer

IntroductionAldo-keto reductase 1B10 (AKR1B10) is a multifunctional enzyme, which is important in cancer development and progression, but the landscape of AKR1B10 in pan-cancers and in tumor microenvironment is unclear.MethodThis study integrated the sequencing data of 33 cancer types, including gastric cancer, from TCGA project to explored the expression pattern and genetic and epigenetic alterations of AKR1B10. The association of AKR1B10 expression with clinical progression of cancers was evaluated by Kaplan-Meier analysis; the potential role of AKR1B10 in tumor microenvironment (TME) and immune-related gene expression were analyzed by PURITY, ESTIMATE, TIMER and CIBERSORT algorithms. The expression of AKR1B10 and immune cell markers in gastric cancer were evaluated with multiplex immunofluorescence staining.ResultResults indicated that AKR1B10 was highly expressed in the gastrointestinal tract in health donors, but the expression of AKR1B10 was significantly changed in most of cancer types, which may be ascribed to DNA methylation in its promoter. The AKR1B10 expression in cancers and its value in disease progression was bidirectional and functionally enriched in metabolism in pan-cancers. In tumor microenvironment, AKR1B10 was significantly correlated with immune cell infiltrations and immune gene expression. In the stomach, along with the diminishing of AKR1B10 expression, CD68+ macrophage increased and CD19+ B cell decreased in gastric cancer.DiscussionThese data indicates that AKR1B10 may be an important factor in the development and progression and a potential therapeutic target for multiple cancers, but plays as a protector in the gastric tissues.

Hypoxia reconstructed colorectal tumor microenvironment weakening anti-tumor immunity: construction of a new prognosis predicting model through transcriptome analysis

BackgroundHypoxia in the tumor microenvironment (TME) plays a pivotal role in the progression and prognosis of colorectal cancer (CRC). However, effective methods for assessing TME hypoxia remain lacking. This study aims to develop a novel hypoxia-related prognostic score (HPS) based on hypoxia-associated genes to improve CRC prognostication and inform treatment strategies.MethodsTranscriptomic data from CRC patients were analyzed using Lasso regression to identify hypoxia-associated genes with the strongest prognostic significance. The identified genes were validated in vitro by assessing their expression under normoxic and hypoxic conditions in normal intestinal epithelial cells and CRC tumor cell lines. Functional relevance was explored through differential gene expression analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network construction. The association of HPS with extracellular matrix (ECM) composition, immune cell infiltration, and immune suppression was also investigated.ResultsSeven hypoxia-associated signature genes were identified, each demonstrating a strong correlation with CRC prognosis. The hypoxia-related prognostic score (HPS), derived from these genes, was significantly linked to changes in the TME. Specifically, HPS values were associated with alterations in ECM composition and distinct immune cell infiltration patterns. Higher HPS values corresponded to increased infiltration of immune-suppressive cells and reduced presence of anti-tumor immune cells. This imbalance promoted an immune-suppressive TME, facilitating tumor progression and immune evasion.ConclusionsThe hypoxia-related prognostic score (HPS) captures the regulatory influence of TME hypoxia on immune responses, offering valuable insights into its role in tumor progression. HPS holds promise as a prognostic tool and a guide for developing personalized treatment strategies in CRC.

Tumor-infiltrating lymphocytes in melanoma: from prognostic assessment to therapeutic applications

Malignant melanoma, the most aggressive form of skin cancer, is characterized by unpredictable growth patterns, and its mortality rate has remained alarmingly high over recent decades, despite various treatment approaches. One promising strategy for improving outcomes in melanoma patients lies in the early use of biomarkers to predict prognosis. Biomarkers offer a way to gauge patient outlook early in the disease course, facilitating timely, targeted intervention. In recent years, considerable attention has been given to the immune response’s role in melanoma, given the tumor’s high immunogenicity and potential responsiveness to immunologic treatments. Researchers are focusing on identifying predictive biomarkers by examining both cancer cell biology and immune interactions within the tumor microenvironment (TME). This approach has shed light on tumor-infiltrating lymphocytes (TILs), a type of immune cell found within the tumor. TILs have emerged as a promising area of study for their potential to serve as both a prognostic indicator and therapeutic target in melanoma. The presence of TILs in melanoma tissue can often signal a positive immune response to the cancer, with numerous studies suggesting that TILs may improve patient prognosis. This review delves into the prognostic value of TILs in melanoma, assessing how these immune cells influence patient outcomes. It explores the mechanisms through which TILs interact with melanoma cells and the potential clinical applications of leveraging TILs in treatment strategies. While TILs present a hopeful avenue for prognostication and treatment, there are still challenges. These include understanding the full extent of TIL dynamics within the TME and overcoming limitations in TIL-based therapies. Advancements in TIL characterization methods are also critical to refining TIL-based approaches. By addressing these hurdles, TIL-focused research may pave the way for improved diagnostic and therapeutic options, ultimately offering better outcomes for melanoma patients.

Global research progress of nanomedicine and colorectal cancer: a bibliometrics and visualization analysis

BackgroundSurgery and chemoradiotherapy are the main clinical treatment methods for colorectal cancer (CRC), but the prognosis is poor. The emergence of nanomedicine brings bright light to the treatment of CRC. However, there has not been a comprehensive and systematic analysis of CRC and nanomedicine by bibliometrics.MethodsWe searched the Web of Science Core Collection database (WOSCC) for relevant literature published from 2011 to 2024. We used VOSviewer and Citespace to analyze countries, institutions, authors, keywords, highly cited references, and co-cited references.Results3105 pieces of literatures were included in the research analysis, and PEOPLES R CHINA and the USA took the leading position in the number of papers published and had academic influence. The Chinese Academy of Sciences posted the most papers. The most prolific scholar was Abnous Khalil. The level of economic development is inversely proportional to the number of cases and deaths of colorectal cancer. Nanoparticles (NPs), the nanomedical drug delivery system (NDDS) is a hot topic in the field. Photodynamic therapy (PDT), immunogenic cell death (ICD), tumor microenvironment (TEM), folic acid, and pH are the cutting edge of the field.ConclusionThis paper introduces the research hotspot, emphasis, and frontier of CRC and nanomedicine, and points out the direction for this field.

Integrative multi-omics analysis reveals a novel subtype of hepatocellular carcinoma with biological and clinical relevance

BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.MethodsWe integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model. Proteomic analysis validated the TP-TME-related signatures. Joint analysis of scRNA-seq and ST-seq revealed characteristic clusters associated with TP high-risk subtypes, and immunohistochemistry confirmed the expression of key genes. We conducted functional enrichment analysis, transcription factor activity inference, cell-cell interaction, drug efficacy analysis, and mutation information analysis to identify a novel subtype of HCC.ResultsOur analyses constructed a robust HCC prognostic risk prediction model. The patients with TP-TME high-risk subtypes predominantly exhibit hypoxia and activation of the Wnt/beta-catenin, Notch, and TGF-beta signaling pathways. Furthermore, we identified a novel subtype, XPO1+Epithelial. This subtype expresses signatures of the TP risk subtype and aligns with the biological behavior of high-risk patients. Additional analyses revealed that XPO1+Epithelial is influenced primarily by fibroblasts via ligand-receptor interactions, such as FN1-(ITGAV+ITGB1), and constitute a significant component of the TP-TME subtype. Moreover, XPO1+Epithelial interact with monocytes/macrophages, T/NK cells, and endothelial cells through ligand-receptor pairs, including MIF-(CD74+CXCR4), MIF-(CD74+CD44), and VEGFA-VEGFR1R2, respectively, thereby promoting the recruitment of immune-suppressive cells and angiogenesis. The ST-seq cohort treated with Tyrosine Kinase Inhibitors (TKIs) and Programmed Cell Death Protein 1 (PD-1) presented elevated levels of TP and TME risk subtype signature genes, as well as XPO1+Epithelial, T-cell, and endothelial cell infiltration in the treatment response group. Drug sensitivity analyses indicated that TP-TME high-risk subtypes, including sorafenib and pembrolizumab, were associated with sensitivity to multiple drugs. Further exploratory analyses revealed that CTLA4, PDCD1, and the cancer antigens MSLN, MUC1, EPCAM, and PROM1 presented significantly increase expression levels in the high-risk subtype group.ConclusionsThis study constructed a robust prognostic model for HCC and identified novel subgroups at the single-cell level, potentially assisting in the assessment of prognostic risk for HCC patients and facilitating personalized drug therapy.

Extracellular nicotinamide phosphoribosyltransferase visfatin activates JAK2-STAT3 pathway in cancer-associated fibroblasts to promote colorectal cancer metastasis.

Metastasis is one of the major challenges in the treatment of colorectal cancer (CRC), during which cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critically involved. In this study, we aim to explore the regulatory role of extracellular nicotinamide phosphoribosyltransferase Visfatin and its impact on CRC metastasis. To examine the effect of visfatin on CAFs, human CRC tissue-derived CAFs were exposed to visfatin, and the expression of inflammatory factors, activation of JAK-STAT pathway and production of ROS in CAFs were assessed. To examine the effect of visfatin-treated CAFs on CRC metastasis, human CRC cell line SW480 or SW620 were cultured with the conditioned medium derived from visfatin-treated CAFs, and the invasion and migration ability of SW480 or SW620 cells were evaluated by transwell migration and matrigel invasion assays. Our previous study found that visfatin, a secreted form of nicotinamide phosphoribosyltransferase that governs the rate-limiting step of NAD synthesis, promoted CRC metastasis. However, little is known about the effect of visfatin on CAFs. The conditioned medium derived from visfatin- treated CAFs promotes the migratory and invasive capability of CRC cells, and enhance lung metastasis in mouse model. Visfatin treatment stimulated the expression of a couple of inflammatory factors in CAFs, which was mediated by visfatin-induced activation of JAK- STAT pathway and accumulation of ROS. Inhibition of JAK-STAT pathway or neutralization of cellular ROS attenuated visfatin-mediated migration and invasion of CRC cells. The present work highlights a critical role of visfatin in the crosstalk between CRC cells and CAFs, which moonlight as a non-metabolic extracellular signal molecule to hijacks JAK-STAT pathway in CAFs to promote CRC metastasis.