Search Results (130)

Colorectal cancer (CRC) is a major cause of cancer death, with the tumor microenvironment and gene expression influencing outcomes. Identifying survival-associated epithelial marker genes (EMGs) may improve prognosis and guide therapy. We obtained single-cell RNA-sequencing (scRNA-seq) data from CRC patients (n = 23,176 cells) from the TISCH database to identify EMGs through differential expression analysis. These were intersected with malignant cell markers. We used bulk RNA-seq data from TCGA-COAD (n = 375) to assess EMG prognostic value via univariable Cox analysis, followed by LASSO regression. Significant genes were evaluated using multivariable Cox models. An EMGs-based risk score was developed and validated using GSE39582 (n = 585) and GSE17536 (n = 177). Immune infiltration was assessed using xCELL and TIMER algorithms. A total of 107 EMGs were identified and assessed in TCGA data. Cox analysis identified 18 survival-related EMGs, which were narrowed by LASSO to SPINK1 and TIMP1. Multivariable analysis confirmed SPINK1 (HR: 0.88, 95% CI: 0.79–0.97, p = 0.009) and TIMP1 (HR: 1.66, 95% CI: 1.29–2.13, p < 0.001) as independent survival predictors. Patients were classified into high- (n = 187) and low-risk (n = 188) groups. The low-risk group had significantly better overall and disease-free survival. Immune profiling revealed distinct patterns, where the high-risk group showed higher dendritic cells, memory T-cells, macrophages, and immune checkpoint expression, while the low-risk group showed enrichment of NK cells, plasma cells, and CD4+ T-helper cells. These findings were validated in the GSE39582 and GSE17536 cohorts. EMGs have prognostic value in CRC, with SPINK1 and TIMP1 as independent survival predictors. Distinct immune patterns support integrating EMGs with immune profiling for improved risk stratification and personalized treatment. Full article

Background: Intratumour heterogeneity (ITH) is one of the key characteristics of cancer and is closely associated with patient prognosis, treatment resistance, and tumor metastasis. Nevertheless, the study of ITH in hepatocellular carcinoma (HCC) remains limited. Methods: The present study elucidated the influence of ITH on the tumor microenvironment (TME) in HCC. We applied Non-negative Matrix Factorization (NMF) analysis to a cohort of 78 single-cell RNA sequencing (scRNA-seq) HCC samples to systematically characterize ITH. Furthermore, by integrating spatial transcriptomics (ST) data from five HCC patients, we comprehensively analyzed the spatial organization and functional properties of distinct niches within HCC. We conducted a detailed analysis of the cell-type co-localization relationships within the TME and constructed a comprehensive atlas of HCC spatial organization. Results: We observed a co-localization relationship between hypoxia tumor cells, plasmalemma vesicle-associated protein (PLVAP⁺) endothelial cells (EC), and vascular endothelial growth factor A (VEGFA⁺) cancer-associated fibroblasts (CAF), suggesting a key role for hypoxia tumor cells in VEGFA⁺ CAF transformation and tumor angiogenesis. We identified a unique boundary region enriched with dendritic cells1 (DC1), interferon-expressing tumor cells, lymphatic EC, C–X–C Motif Chemokine Ligand 10 (CXCL10⁺) macrophages (Mac), and secreted phosphoprotein 1 (SPP1⁺) Mac located between the tumor-infiltrating immune cells and tumor regions. Furthermore, we found that CXCL10⁺ Mac and SPP1⁺ Mac, despite co-localizing in the boundary region, exhibit distinct functions, which may be attributed to their unique spatial locations, with the former being closer to the immune-infiltrated region and the latter more proximal to the tumor area. Conclusions: Our study highlights the critical role of spatial interactions between tumor cells and the microenvironment in HCC. The findings offer new insights into ITH and underscore the importance of spatial organization in understanding cancer biology and designing future precision therapies. Full article

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors. Full article

Exosomes are extracellular vesicles that play a central role in mediating intercellular communication within the tumor microenvironment (TME). Cancer-derived exosomes carry proteins, nucleic acids, and lipids that reshape the phenotype and function of surrounding stromal and immune cells, thereby promoting tumor progression, angiogenesis, metastasis, and resistance to therapy. At the same time, exosomes derived from TME components, including macrophages, dendritic cells, B cells, T cells, fibroblasts, neutrophils, and NK cells, reciprocally influence tumor growth and immune evasion. These bidirectional interactions highlight exosomes as both drivers of tumor progression and regulators of antitumor immunity. In this review, we synthesize current evidence on the diverse mechanisms by which exosomes reprogram immune and stromal cells, with a focus on their dual roles in cancer biology. We also discuss emerging therapeutic strategies to inhibit exosome biogenesis, release, and function, underscoring their translational potential as novel targets for cancer diagnosis and treatment. Full article

Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor α (solTNFα) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNFα-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling. Full article

Tumor-infiltrating lymphocytes (TILs) are thought to play important roles in tumor shrinkage and survival prolongation in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). TILs are mononuclear immune cells such as lymphocytes and plasma cells, including CD4+ and CD8+ T cells, natural killer cells, B cells, macrophages, regulatory T cells (Tregs), and myeloid/dendritic cells. The pre-NAC presence of more T cells and fewer Tregs in biopsy samples of primary breast tumors is known to contribute to tumor shrinkage and prolonged survival. This review was conducted to elucidate these roles in patients with breast cancer treated with NAC. Publications selected for inclusion in this review were identified by a PubMed search for articles published in English, performed using the terms “breast cancer”, “neoadjuvant chemotherapy”, “tumor-infiltrating lymphocyte”, “pathological complete response”, and “immune response”. The search was completed in July 2024. The functional roles of TILs in the achievement of these outcomes may vary by tumor subtype; increases and decreases in TIL levels before and after NAC have been shown to have conflicting effects. Biomarkers have been reported to predict local responses in the tumor microenvironment (e.g., immune-related gene signatures) and systemic immune responses (e.g., neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios). Immune gene signatures and immune cell infiltration do not appear to be universally associated with tumor response or outcome in patients with breast cancer treated with NAC. The functional roles of TILs in breast tumor response and breast cancer survival may vary by tumor subtype, and conflicting results for the same subtypes may be due to differences in NAC regimens, immune responses, tumor heterogeneity, sample size, and the technical methods used to evaluate TILs in tumor samples. Full article

Tissue inhibitor of metalloproteinase 3 (TIMP3) serves as a prominent endogenous inhibitor of matrix metalloproteinases (MMPs), playing a crucial role in inhibiting metastasis, and angiogenesis. However, its exact contributions to colorectal cancer (CRC) remain largely unidentified. We aimed to ascertain the prognostic significance of TIMP3 in CRC patients through a bioinformatic approach. GEPIA, UALCAN, Kaplan–Meier plotter, LinkedOmics, cBioPortal, GeneMANIA, TIMER, TISIDB, the ScTIME database, TISMO, TIDE, CAMOIP, and TISCH2 were employed to comprehensively analyze the differential expression, prognostic value, genetic alterations, signaling pathways, immune cell infiltration, tumor microenvironment (TME) and associated genes of TIMP3 in CRC patients. Compared to adjacent normal tissues, we observed a significant downregulation of TIMP3 expression in CRC samples. Gene interaction networks elucidated that TIMP3 and its associated genes play a pivotal role in cancer progression, particularly in processes critical to colorectal cancer, such as extracellular matrix organization and angiogenesis. Analysis of the TME further indicates that TIMP3 expression was intricately associated with diverse immune cell types infiltration levels, chemokines, and immunomodulators. Most importantly, those with elevated TIMP3 expression had improved immunological scores. Moreover, TIMP3 exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, dendritic cells, and fibroblasts. Furthermore, improved immunotherapeutic responses against PD-1/PD-L1 were linked to elevated TIMP3 levels. In TIMP3-high groups, there was a considerable increase in IL10, PDCD1, CD80, CXCL9, and CXCR3. This highlights the extensive influence of TIMP3 downregulation on the immune milieu within CRC. Our findings emphasize the multifaceted involvement of TIMP3 in CRC, not only influencing the molecular pathways associated with cancer progression, but also intricately shaping the immune microenvironment. As a result, TIMP3 appears promising as a potential CRC therapeutic target. Full article

Lactobacillus species play a fundamental role in maintaining a healthy vaginal microbiota and have been increasingly recognized for their protective effects against high-risk human papillomavirus (HR-HPV) infection and the progression of cervical intraepithelial neoplasia (CIN). These beneficial bacteria contribute to host defense through multiple mechanisms, including the production of lactic acid that sustains a low vaginal pH, enhancement of epithelial barrier integrity via E-cadherin regulation, and modulation of immune signaling pathways such as interferon responses and NF-κB activity. Lactobacillus strains exert anti-inflammatory effects by downregulating pro-inflammatory cytokines and interfering with oncogenic pathways including Wnt/β-catenin and the expression of HPV E6 and E7 proteins. Additionally, they may regulate tumor-suppressor microRNAs and modulate dendritic cell and macrophage activity, supporting antiviral immunity. Recent studies have explored their potential influence on CIN regression and HR-HPV clearance, particularly the strains Lactobacillus crispatus and L. gasseri, which are associated with favorable microbial community states. This review explores the potential mechanisms through which Lactobacillus species contribute to HR-HPV clearance and the regression of cervical dysplasia, integrating evidence from molecular studies, in vivo models, and clinical trials. The emerging role of probiotic interventions as adjunctive strategies in HPV management is also discussed, highlighting their possible synergy with conventional treatments and prophylactic vaccination. Full article

The human Poly ADP-ribose Polymerase (PARP) family comprises 17 enzymes responsible for the transfer of ADP-ribose to proteins, forming poly- or mono-ADP-ribosylation. This post-translational modification regulates DNA repair and programmed cell death, processes affecting cancer biology. PARP inhibitors, including the FDA-approved olaparib, are used to treat BRCA-dependent breast and ovarian cancers. Although therapies with use of PARP inhibitors are showing clinical success, their effects on the immune system remain understudied. Prior work has shown that PARP inhibition can modulate inflammatory responses and alter innate immunity. In this study, we evaluated the immunomodulatory effects of olaparib on myeloid cells in vivo, focusing on bone marrow and spleen. Olaparib treatment altered the composition and activation state of dendritic cells, neutrophils, and macrophages. In the bone marrow, olaparib increased the proportion of cDC2 population, mature neutrophils and inflammatory macrophages expressing CD80. In contrast, splenic myeloid cells exhibited enhanced expression of markers associated with tolerogenic phenotypes, including CD206 and CD124 in neutrophils and macrophages. The spleen also showed an increase in immature monocyte-derived dendritic cells (CD206+) and a bias toward the cDC2 subset. These findings indicate that PARP inhibition can induce short-term phenotypic remodeling of myeloid cell populations, promoting a more immunoregulatory profile, especially in the spleen. These changes may contribute to an altered immune landscape with implications for anti-tumor immunity. Full article

This review delves into the characteristics of lipid metabolism reprogramming in cancer cells and immune cells within the tumor microenvironment (TME), discussing its role in tumorigenesis and development and analyzing the value of lipid metabolism-related molecules in tumor diagnosis and prognosis. Cancer cells support their rapid growth through aerobic glycolysis and lipid metabolism reprogramming. Lipid metabolism plays distinct roles in cancer and immune cells, including energy supply, cell proliferation, angiogenesis, immune suppression, and tumor metastasis. This review focused on shared lipid metabolic enzymes and transporters, lipid metabolism-related oncogenes and non-coding RNAs (ncRNAs) involved in cancer cells, and the influence of lipid metabolism on T cells, dendritic cells (DCs), B cells, tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), and natural killer cells (NKs) within TME. Additionally, the role of lipid metabolism in tumor diagnosis and prognosis was explored, and lipid metabolism-based anti-tumor treatment strategies were summarized, aiming to provide new perspectives for achieving precision medicine. Full article

Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated ΔM062R MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with ΔM062R confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that ΔM062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit, likely through promoting tumor antigen-specific T cell function. Moreover, we also tested ΔM062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that ΔM062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4⁺ T cells. Overall, ΔM062R presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine. Full article

Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune–tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies. Full article

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

This study aims to investigate the prognostic impact of cellular components of the tumor microenvironment (TME), analyzed through immunohistochemistry, in oral squamous cell carcinoma (OSCC). This review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Searches were performed in EMBASE, Medline/PubMed, Cochrane Collaboration Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. After applying the study criteria, 59 articles were included, involving the analysis of cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. It was found that TME rich in α-SMA-positive CAFs, tumor-associated macrophages, and dendritic cells contribute to the invasion and progression of OSCC, resulting in a poorer prognosis. In contrast, the presence of high amounts of NK CD57⁺ cells, CD8⁺/CD45RO⁺ T cells, and PNAd⁺ endothelial cells are associated with anti-tumor immune responses in OSCC and improved survival rates. CD3⁺ and CD4⁺ T cells, Treg cells, B cells, and mast cells have shown little to no evidence of prognostic utility. Several stromal components of TME were found to have a strong impact on the aggressiveness of OSCC, reaffirming the potential use of these biomarkers as prognostic tools and therapeutic targets. Full article