Oral squamous cell carcinoma (OSCC) is a prevalent malignant tumor of the head and neck, characterized by an immunosuppressive tumor microenvironment. The traditional treatment approach for OSCC typically involves a combination of surgical resection, radiotherapy, and chemotherapy. Over the last few decades, the 5-year overall survival rate for OSCC has remained relatively stagnant at approximately 50-60%. Recently, the rapid progress in immunotherapy has revolutionized OSCC treatment, particularly through the use of immune checkpoint blockade therapies. Nivolumab and pembrolizumab have been approved by the US Food and Drug Administration (FDA) for the immunotherapy of head and neck squamous cell carcinoma (HNSCC). Additionally, other modalities such as costimulatory agonists, adoptive cellular therapy, cytokine immunotherapy, cancer vaccines, and photoimmunotherapy have shown promising feasibility and efficacy in relevant preclinical and clinical studies. Future directions for OSCC immunotherapy include precision medicine and research into the pathogenesis of immune-related adverse events (irAEs) and standardization of management methods. Furthermore, nano-immunotherapy is expected to be a significant trend in OSCC treatment. Clinical trial number Not applicable.
Background: While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in gastric cancer (GC) remains limited, underscoring the need for mechanistic biomarkers of immune evasion.
Methods: We analyzed m1A RNA modification patterns in the TCGA-STAD cohort, stratifying patients into three subtypes. Functional assays (including CRISPR-based SFRP2 modulation, NFAT/TOX reporter systems, and ex vivo T-cell exhaustion models) were employed to dissect the m1A-SFRP2-NFAT/TOX axis.
Results: High-m1A tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3+PD-1+ T cells and poor ICIs responses. Mechanistically, m1A-modified transcripts stabilized SFRP2, which activated NFAT1/2-TOX signaling to drive T-cell dysfunction-independent of PD-L1 or TMB. SFRP2 overexpression induced irreversible T-cell exhaustion, while its blockade restored antitumor immunity in preclinical models.
Conclusion: Our study unveils m1A-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The m1A scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.
Clinical trial number: Not applicable.
Background: CAR-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its effectiveness against solid tumors remains limited due to tumor antigen heterogeneity. NKG2DLs, including MICA/B and the ULBP family, are stress-induced molecules frequently upregulated on the surface of tumor cells and components of the tumor microenvironment, providing attractive targets for immunotherapy. To broaden the targeting capability beyond conventional Claudin18.2-directed CAR-T cells, we engineered a Synthetic NKG2D Receptor (SNR). The SNR comprises the extracellular domain of NKG2D fused with the intracellular signaling domains of DAP10 and DAP12, enabling effective targeting of NKG2D ligands (NKG2DLs).
Methods: Expression of NKG2DLs and CLDN18.2 were detected by immunohistochemistry on a gastric cancer tissue microarray. We designed SNR CAR-T cells by linking CLDN18.2 CAR with SNR by a 2A self-cleaving peptide. We assessed their cytotoxicity, tumor infiltration, persistence, and antitumor efficacy using in vitro assays, patient-derived xenograft (PDX) models, and murine syngeneic models. Additionally, transcriptomic analysis and flow cytometry were performed to evaluate exhaustion and memory markers.
Results: SNR CAR-T cells demonstrated enhanced cytotoxicity against tumor cells with heterogeneous CLDN18.2 expression, effectively lysing both CLDN18.2-positive and NKG2DL-positive tumor cells in vitro. In PDX and murine models, SNR CAR-T cells exhibited superior antitumor efficacy, leading to significant tumor regression and CAR-T expansion compared to conventional CAR-T cells. Furthermore, SNR CAR-T cells displayed reduced expression of exhaustion markers and increased expression of memory-associated markers. Enhanced tumor infiltration, proliferation and cytotoxicity within the tumor microenvironment, and a reduced presence of myeloid-derived suppressor cells (MDSCs) and tumor neovasculature were observed. Importantly, SNR CAR-T cell therapy was well-tolerated, with no significant toxicity noted in all the treated animals.
Conclusion: The SNR CAR-T cell approach addresses tumor antigen heterogeneity and suppressive tumor microenvironment, offering a promising therapeutic strategy for solid tumors and paving the way for its future clinical applications.
Purpose: The tumor microenvironment (TME) plays a crucial role in cancer progression. Cancer-associated fibroblasts (CAFs) are key components of the TME and play critical roles in tumor development and metastasis. However, the mechanisms by which CAFs influence hepatocellular carcinoma (HCC) metastasis are not fully understood.
Methods: Extracellular vesicles (EVs) from CAFs and normal fibroblasts (NFs) were characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. An iTRAQ-based proteomic sequencing analysis was conducted to quantify proteins in the EVs from these cells. Colony formation assays and Transwell assays were used to assess tumor cell proliferation and migration. Xenograft tumor models were established in nude mice to evaluate tumor progression in vivo. Coimmunoprecipitation and molecular docking were performed to explore the interactions between CTGF and Notch1.
Results: A high CAF abundance is associated with poor prognosis in HCC patients. EVs from CAFs significantly enhanced the proliferative and invasive abilities of HCC cells in vitro and in vivo. Connective tissue growth factor (CTGF) was found to be highly upregulated in CAF-derived EVs, and CTGF knockdown in CAF-derived EVs attenuated their tumor-promoting capacities. Mechanistically, CTGF derived from CAF-EVs activated the Notch1/Snail1 signaling pathway in recipient cells via interaction with the Notch1 receptor, enhancing HCC cell proliferation and invasion. Furthermore, high CTGF expression was significantly correlated with poor clinicopathological features in HCC patients.
Conclusion: Our findings revealed that CTGF derived from CAF-EVs promoted the proliferation and invasion of HCC cells via activation of the Notch1/Snail1 pathway, highlighting CTGF derived from CAF-EVs as a prognostic biomarker and therapeutic target in HCC.
Abnormal post-translational modifications (PTMs) play a crucial role in tumor initiation and progression. However, the mechanisms by which lncRNAs, as emerging epigenetic regulators, mediate PTMs remain largely unexplored. This review provides a comprehensive summary of the latest research on the interplay between lncRNA-mediated PTMs and tumorigenesis. We delve into the molecular mechanisms underlying these interactions, focusing on how lncRNAs regulate PTMs to influence tumor progression. We place particular emphasis on the lncRNA-mediated PTMs as a driver of therapeutic resistance, shedding light on its potential as a novel target for cancer intervention. Furthermore, we highlight the therapeutic potential of targeting lncRNA-PTM networks, emphasizing novel RNA-based strategies and their clinical relevance in cancer treatment. We believe that an in-depth understanding of lncRNA-mediated PTMs could uncover novel therapeutic targets, paving the way for innovative approaches in cancer diagnosis and treatment.
Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs-including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism-such as inhibition of SCD1, CPT1A, and HMG-CoA reductase-have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.
Background: Fbxo2 is part of the SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase complex. While increasing evidence indicates that Fbxo2 influences tumorigenesis and progression in various human malignancies, its biological importance and molecular mechanisms in renal cell carcinoma (RCC) are poorly understood.
Methods: Bioinformatic analysis of publicly available datasets was utilized to determine the association between Fbxo2 expression and survival in RCC patients. CCK8, colony-formation, and EdU assays were carried out to measure cell proliferation after Fbxo2 modulation in RCC cells. Coimmunoprecipitation, mass spectrometry, Western blotting, and ubiquitin assays were performed to explore the molecular mechanism of Fbxo2-involved tumorigenesis in RCC.
Results: Fbxo2 suppresses RCC cell growth. Moreover, higher Fbxo2 expression was positively associated with improved overall survival in RCC patients. In RCC, Fbxo2 inhibition increased cell motility and proliferation and inhibited cell apoptosis. WEE1 was identified as a novel substrate of Fbxo2 in RCC. Fbxo2 binds to the kinase domain of WEE1 through its FBA domain. Consistently, in xenograft mouse models, Fbxo2 knockdown increased tumor growth, whereas WEE1 depletion partially abolishes the tumorigenic effects caused by Fbxo2 silencing in vivo.
Conclusions: Our research revealed that Fbxo2 impedes the progression of RCC by interacting with WEE1, promoting its ubiquitination and degradation. Therefore, targeting the Fbxo2/WEE1 axis may represent a promising therapeutic strategy for treating RCC.
Purpose: Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.
Method: SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.
Results: Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.
Conclusion: HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.
Background: Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient's immune system is severely impaired, which increases the patient's susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.
Methods: We constructed two sepsis-melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.
Results: We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8+T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.
Conclusion: Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8+ T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.
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