Current Cancer Drug Targets - Volume 25, Issue 10, 2025

The most prevalent histologic subtype of primary liver cancer, hepatocellular carcinoma, is also the third most lethal malignancy worldwide and a significant cause of cancer death. When diagnosed, it is frequently too late for curative therapies. To add to the difficulty, it is resistant to conventional systemic therapies like chemotherapy.

Recently, more attention has been given to the use of immunotherapy for this condition. Immunotherapy has had a major impact on the outcome of several malignancies; several studies have revealed the potential role of immunotherapy in advanced hepatocellular carcinoma. To provide an overview of the current literature, justification, and clinical evidence for the use of immunotherapy in advanced hepatocellular carcinoma, we employed a systematic literature review (SLR) approach in this work. Additionally, we explored the benefits and rationales of various treatment combinations and described the molecular mechanisms behind resistance to a number of immunotherapy drugs.

A total of 188 articles from credible journals published between 2013 and August 7, 2023, were screened. Eight of those articles were chosen for in-depth study. This systematic review concluded that the current immunotherapeutic approaches have the potential to improve outcomes for aHCC patients; however, several clinical and biological hurdles have to be overcome, and predictive markers are still eagerly needed.

To fully realize the potential of immunotherapy agents and their combination therapies to enhance health outcomes for patients with aHCC, additional investigation and research are required.

This study aimed to analyze the expression of Matrix Metalloproteinase 7 (MMP7) and molecular mechanism at the Transcription Factor (TF) level in Oral Squamous Cell Carcinoma (OSCC).

MMP7 expression was preliminarily explored in Head and Neck Squamous Cell Carcinoma (HNSCC) in the online database, followed by functional analysis and prediction of TF of MMP7. IHC was employed to detect MMP7 levels in OSCC samples. SCC9 and 293T cells were used to explore the transcriptional and regulatory effects of predicted TF on MMP7 by reporter double luciferase assay, RT-qPCR, western blotting, and cellular immunofluorescence. Transwell and TUNEL were employed to detect the migration and apoptosis.

MMP7 was significantly up-regulated in HNSCC and OSCC tissues. Moreover, MMP7 was positively correlated with CAFs and significantly enriched in the signaling pathway of RNA degradation. The c-Jun pathway was also up-regulated in OSCC tissues, and predicted to be optimal TF of MMP7 with positive regulatory relationship. In OSCC, silencing and over-expression of c-Jun significantly decreased and increased the level of MMP7. Meanwhile, c-Jun affected the behavior of SCC9 cells, which showed that after c-Jun gene silencing, the ability of cell migration was weakened, while apoptosis was enhanced. When c-Jun gene was overexpressed, the migration ability was enhanced, but apoptosis was not significantly affected.

MMP7 has been proven to be a key protein in the development of OSCC, and has the potential to become a biological marker and therapeutic target. It has been found that c-Jun could bind to the MMP7 promoter region, and the silencing or overexpression of c-Jun can positively regulate the expression of MMP7.

Ferroptosis is closely related to radiotherapy resistance in multiple cancers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferroptosis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated.

Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were established. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe²⁺ levels were measured by ELISA kits. The molecular interaction was analyzed using ChIP and MSP assays.

Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly expressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 reduced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanistically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to reduced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knockdown.

MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.

The heterogeneity of breast cancer requires exploring novel prognostic biomarkers as well as therapeutic targets for the treatment of the disease.

The METABRIC dataset was used to describe the gene expression of the programmed death-ligand 1 (PD-L1) and the hepatocyte growth factor receptor (MET) and their association with the tumor clinicopathologic characteristics and overall survival in breast cancer.

The expression of the PD-L1 and MET genes correlated positively with the Nottingham Prognostic Index (NPI) (p=0.003 and p < 0.001, respectively). The expression of the two genes correlated inversely in patients with luminal A and luminal B tumors (r= – 0.089, p= 0.021 and r= – 0.116, p= 0.013, respectively). The PD-L1 mRNA levels were significantly higher in hormone receptor-negative and HER2-positive tumors. MET mRNA expression levels were significantly higher in hormone receptor-negative, HER2-enriched, and non-luminal breast cancers. The PD-L1/MET double-high expression was associated with younger age of patients at diagnosis, higher NPI scores, larger tumors, advanced stage, high-grade, hormone receptor-negativity, HER2-positivity, and non-luminal tumors. None of the genes or their double expression status was significantly associated with overall survival in this analysis.

The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

This study aimed to investigate the expression pattern of phosphatidylinositol 3-kinase class III (PIK3C3/vps34) in gastric cancer (GC) tissues and their juxtaposed normal counterparts and its correlation with the clinicopathological attributes and prognostic outlook of afflicted individuals.

Immunohistochemical (IHC) staining was used to ascertain the expression levels of PIK3C3/vps34 across 60 GC tissues juxtaposed with their normal counterparts. Statistical methodologies were used to scrutinize the correlation between PIK3C3/vps34 expression and clinicopathological features, along with prognostic implications for GC patients.

In GC tissues, the positive expression rate of PIK3C3/vps34 was 23.3% (14/60), which contrasted sharply with the markedly elevated rate of 66.7% (40/60) observed in adjacent tissues. The positive expression proportion of PIK3C3/vps34 within GC tissues exhibited a notable decrease than in adjacent tissues (P < 0.05). The expression of PIK3C3/vps34 inversely correlated with tumor size, degree of tissue differentiation, depth of tumor infiltration, and incidence of lymph node metastasis (P < 0.05), whereas no significant associations were found with patient sex, age, tumor location, TNM staging, or distant metastasis (P > 0.05). As the tumor diameter increases, the degree of tissue differentiation diminishes, tumor infiltration depth intensifies, lymph node metastasis emerges, the TNM stage progresses, and PIK3C3/vps34 expression level within GC tissues declines correspondingly. Kaplan-Meier survival analysis unveiled a prolonged survival duration among GC patients exhibiting heightened PIK3C3/vps34 expression than in their counterparts with diminished expression (HR=0.66, 95% CI: 0.55-0.80), demonstrating statistical significance (P < 0.05). Protein interaction analysis revealed noteworthy interactions involving PIK3C3 with Beclin 1, UVRAG, and ATG14.

PIK3C3/vps34 is downregulated in GC tissues, exerting a pivotal role in tumorigenesis, and is intimately linked with the prognostic trajectory of GC patients. It may serve as a significant biomarker for prognostic evaluation and a promising molecular therapeutic target for GC.

This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

In vitro experiments were conducted to explore the effects of ARG on the biological behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autophagy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were assessed.

CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. Western blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax increased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mitochondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmission electron microscopy. ARG inhibited the proliferation and induced the apoptosis of melanoma cells in vivo.

Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.

Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisynthetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was effective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis.

Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m² on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy.

Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy.

Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study contribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy.

ChiCTR1900025659.