CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1Wang, Ju, Du
et alCell Mol Biol Lett (2025) 30 (1), 37
Abstract: Tumor immune escape is a pivotal gateway for esophageal squamous cell carcinoma (ESCC) development. Immune checkpoint-blocking therapies, represented by programmed cell death receptor-1/ligand 1 (PD-1/PD-L1) inhibitors, have achieved remarkable breakthroughs in ESCC treatment. However, not all patients with ESCC receive satisfactory clinical benefit. Therefore, identifying novel biomarkers for predicting the efficacy of immunotherapy in ESCC is of great importance.CircNF1 was screened from the circRNAs microarray, and its expression was measured by droplet digital polymerase chain reaction (ddPCR) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in ESCC tissues and serum. Functional experiments were conducted to demonstrate the role of circNF1 in ESCC proliferation, metastasis, and tumor evasion. High-throughput RNA sequencing, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) were performed to clarify the underlying mechanisms of circNF1-mediated tumor progression.The upregulation of circNF1 was closely associated with the response of anti-PD-L1 immunotherapy. Functionally, circNF1 promoted ESCC cell malignant phenotypes and regulated CD8+ T-cell-mediated antitumor immunity. Mechanistically, circNF1 drove the IL-6-induced oncogenic activation of the JAK-STAT3 pathway, which stimulated p-STAT3 binding of the promoter regions of PD-L1. Furthermore, circNF1 physically interacted with annexin A1 (ANXA1), blocking the ANXA1 deubiquitination induced by ubiquitin-specific protease 7 (USP7), resulting in increased interaction between USP7 and PD-L1 and augmented PD-L1 stability.Our findings provide novel insights into the specific regulatory mechanism of PD-L1 in ESCC cells, which offer a new strategy for synergizing with anti-PD-L1 therapy.© 2025. The Author(s).
Combination therapy with immune checkpoint inhibitors in colorectal cancer: Challenges, resistance mechanisms, and the role of microbiotaRahimi, Baghernejadan, Hazrati
et alBiomed Pharmacother (2025) 186, 118014
Abstract: Colorectal cancer (CRC) is still one of the leading causes of cancer deaths worldwide. Even though there has been progress in cancer immunotherapy, the results of applying immune checkpoint inhibitors (ICIs) have been unsatisfactory, especially in microsatellite stable (MSS) CRC. Single-agent ICIs that target programmed cell death-1 (PD-1)/ PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell Ig- and mucin-domain-containing molecule-3 (TIM-3), and lymphocyte activation gene (LAG)-3 have emerged as having specific benefits. However, many primary and secondary resistance mechanisms are available in the tumor microenvironment (TME) that prevent it from happening. Combination strategies, such as the use of anti-PD-1 and anti-CTLA-4, can be effective in overcoming these resistance pathways, but toxicities remain a significant concern. Moreover, ICIs have been integrated with various treatment modalities, including chemotherapy, radiotherapy, antibiotics, virotherapy, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, and heat shock protein 90 (HSP90) inhibitors. The outcomes observed in both preclinical and clinical settings have been encouraging. Interestingly, manipulating gut microbiota via fecal microbiota transplantation (FMT) has been identified as a new strategy to increase the efficacy of immunotherapy in CRC patients. Therefore, integrating ICIs with other treatment approaches holds promise in enhancing the prognosis of CRC patients. This review focuses on the unmet need for new biomarkers to select patients for combination therapies and the ongoing work to overcome resistance and immune checkpoint blockade.Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Assessment of Cytotoxicity, Impact on Cell Migration and Apoptotic Modulation of Acteoside and Plantamajoside on Human Breast Adenocarcinoma (MCF-7)Cabatit, Carandang, Saragpon
et alAsian Pac J Cancer Prev (2025) 26 (3), 925-934
Abstract: To evaluate the anticancer potential of Acteoside and Plantamajoside using MCF-7 cancer cell line.In this study, the half-maximal inhibitory concentration (IC50) values of Acteoside and Plantamajoside were investigated using the Sulforhodamine B (SRB) assay. The IC50 values of both compounds were utilized in the clonogenic and scratch wound assays to assess cell survival and migration, respectively. The cells with treatments were also analyzed using the Caspase 3/7 assay to determine their capability to induce cell apoptosis. Network Pharmacology was used to evaluate their probable protein targets and pharmacological mechanisms.Acteoside and Plantamajoside exhibited cytotoxic activity against the MCF-7 cancer cell line in vitro, with IC50 values of 134.83 μg/mL and 225.10 μg/mL, respectively. This was further supported by clonogenic assay, which showed a difference in colony formation following treatment with ACT and PMS, compared to the negative control. Specifically, ACT resulted in the formation of only 39.7% of colonies, whereas PMS formed 51.12% of colonies, indicating that these compounds impaired the cells' ability to proliferate and form colonies. Moreover, these compounds were also able to inhibit cell migration as a reduction in the migration area of the MCF-7 cell line was observed. An increase in the percentage of apoptotic cells was also noted post-treatment, which correlated with elevated Caspase 3/7 activity, indicating that these compounds may effectively induce cellular apoptosis. In silico predictions demonstrated that the compounds' anticancer effect may be attributed to their interactions with TLR, PI3K, and STAT-all are implicated in the PD-1 checkpoint pathway and PD-L1 expression in cancer.Both Acteoside and Plantamajoside have demonstrated promising anticancer properties by inhibiting the growth and metastasis of MCF-7 cancer cell line. These compounds induce apoptosis, modulate the PD-1 checkpoint pathway, and influence PD-L1 expression, which may indicate possible molecular mechanisms for their anticancer effects.
Differences in PD-L1, PD-L2, and EGFR Expression Between Naive and Recurrent Tumors in Patients With Head and Neck Squamous Cell Carcinoma: A Retrospective StudySato, Inoue, Wakisaka
et alHead Neck (2025)
Abstract: The efficacy of anti-PD-1 and EGFR therapies for head and neck squamous cell carcinoma (HNSCC) can be predicted using various markers; however, the stability of these markers remains unclear.In this retrospective study, laboratory findings and tissue expression of PD-L1, PD-L2, and EGFR were analyzed in 79 paired naive and recurrent HNSCC tumors. Laboratory findings were also analyzed in nonrecurrent patients using a propensity score-matched analysis. PD-L1 and PD-L2 expression levels were assessed using tumor proportion score (TPS) and combined positive score (CPS), whereas EGFR was evaluated using the H-score.White blood cell, neutrophil, lymphocyte, and monocyte counts and lymphocyte-monocyte ratios were significantly lower in the patients after the first-line treatment regardless of recurrence. PD-L1, PD-L2, and EGFR expression changed in 30%-40% of tumor pairs. Immune but not tumoral PD-L1 positivity rates were significantly higher in the patients with early recurrence.The expression of immune checkpoints including PD-L1 in naive tumors does not reflect those in recurrent tumors. Increasing PD-L1 expression in immune cells may cause early recurrence of HNSCC.© 2025 The Author(s). Head & Neck published by Wiley Periodicals LLC.
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