The tumor microenvironment plays a critical role in the control of metastasis. The epithelial–mesenchymal transition (EMT) is strongly associated with tumor metastasis, and consists of several protein markers, including E-cadherin and vimentin. We discovered that chrysophanol causes oral cancer cell apoptosis and the inhibition of migration/invasion and EMT. However, the detailed mechanisms of chrysophanol and its role in oral cancer with respect to the tumor microenvironment remain unknown. In the clinic, proinflammatory cytokines, such as IL-6 and IL-8, exhibit a higher expression in patients with oral cancer. However, the effect of chrysophanol on the production of IL-6 and IL-8 is unknown. We evaluated the expression of IL-6 and IL-8 in human SAS and FaDu oral cancer cell lines in the presence or absence of chrysophanol. The migration and invasion abilities were also determined using a Boyden chamber assay. Our results showed that treatment with chrysophanol significantly decreased the expression of IL-6 and IL-8, as well as the invasion ability of oral cancer cells. Moreover, chrysophanol also attenuated the EMT by increasing the expression of E-cadherin and reducing the expression of vimentin. Mechanistically, chrysophanol inhibited IL-6- and IL-8-induced invasion and STAT3 phosphorylation. IL-6 and IL-8 promote EMT and cell invasion, which is potentially related to the STAT3 signaling pathway in oral cancer. These findings provide insight into new aspects of chrysophanol activity and may contribute to the development of new therapeutic strategies for oral cancer.

Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD-1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating patients with PDAC. Significance: Autocrine VIP signaling via VPAC2 promotes cancer cell growth and inhibits T-cell function in pancreatic ductal adenocarcinoma, highlighting its potential as a therapeutic target to improve pancreatic cancer treatment.

Breast cancer remains a leading global cause of cancer-related mortality among women, requiring the development of safer and more effective therapeutic strategies. Herbal medicines have gained increasing attention as complementary approaches due to their multi-targeted actions, more limited toxicities, and the potential ability to overcome resistance associated with conventional treatments. This review highlights the antitumor properties and underlying mechanisms of several well-studied herbal compounds, including curcumin, resveratrol, epigallocatechin gallate, withaferin A, thymoquinone, baicalin, berberine, Oldenlandia diffusa, and Salvia miltiorrhiza. These phytochemicals exert antitumor effects by inducing apoptosis, inhibiting cell proliferation and metastasis, modulating immune responses, and sensitizing tumor cells to chemotherapy and radiotherapy. Furthermore, many of these agents regulate key signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells, phosphatidylinositol 3-kinase/AKT, p53, signal transducer and activator of transcription 3, and extracellular signal-regulated kinases 1/2, and the tumor microenvironment. Despite promising preclinical and early clinical evidence, challenges remain regarding the bioavailability, standardization, and large-scale clinical validation of these phytochemicals. This review underscores the therapeutic potential of herbal medicines in breast cancer treatment and advocates for further research to facilitate their integration into evidence-based oncology practice.

Background. Oral cancer belongs to the class of head and neck cancers and can be life threatening if not diagnosed and treated early. Activation of cell death via apoptosis or reactive oxygen species (ROS) accumulation and inhibition of cell cycle progression, migration, and epithelial‐to‐mesenchymal transition (EMT) may be a good strategy to arrest the development of oral cancer. In this study, we analyzed the possible action of chrysophanol isolated from the rhizomes of Rheum palmatum on the oral cancer cell lines FaDu (human pharynx squamous cell carcinoma) and SAS (human tongue squamous carcinoma) by investigating whether chrysophanol could influence cell death. Method. Cell viability was measured by using the MTT assay. For the detection of apoptosis, terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) staining and subG1 population analysis were used. We also examined cell cycle progression and ROS levels by flow cytometry. Additionally, the expression of p53, p21, procaspase 3, cyclin D1, CDK4, cdc2, CDK2, E‐cadherin, vimentin, and PCNA was evaluated by western blotting. Conclusion. Chrysophanol has an anticancer effect on FaDu and SAS cell lines. There is an increase in subG1 accumulation, ROS production, and cell cycle G1 arrest after treatment with chrysophanol. On the other hand, chrysophanol inhibited cell migration/metastasis and EMT. We proposed that chrysophanol may be a good candidate compound on oral cancer treatment in the further.

Oral squamous cell carcinoma (OSCC), a major subtype of head and neck squamous cell carcinoma (HNSCC), is a significant global health burden owing to its late-stage diagnosis and poor prognosis. Recent advancements in molecular biology, genomics, and imaging have transformed the landscape of OSCC diagnosis and treatment. This review provides a comprehensive synthesis of early molecular diagnostic strategies, including biomarker discovery using next-generation sequencing, liquid biopsy, and salivary exosomal microRNAs. In addition, we highlight the emerging role of non-invasive optical imaging technologies and their clinical integration for improved surgical precision and early lesion detection. This review also discusses evolving therapeutic approaches, including immunotherapy, neoadjuvant chemotherapy, and patient-centered multimodal regimens tailored through molecular profiling. We emphasized balancing therapeutic efficacy with the quality of life in patients undergoing chemoradiotherapy. The convergence of multi-omics, artificial intelligence, and precision medicine holds promise for revolutionizing early detection and personalized treatment of OSCC, ultimately improving patient survival and clinical outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes.