Cellular Oncology最新文献

Background: Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments.

Methods: We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions.

Results: MET inhibitors selectively suppressed tumour growth in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC.

Conclusion: Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.

Purpose: Interferon gamma (IFNG) directly affects the antitumor immune response. ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) is also positively correlated with poor prognosis for colorectal cancer (CRC). we performed some works to exploreexplored the underlying mechanism to further understand immune escape in colorectal cancer (CRC).

Methods: First, we used clinical samples to confirm the relationship between ST6GAL1 and CRC. Afterward, we constructed overexpression/knockdown cell lines and performed bulk RNA sequencing, kinase phosphorylation chip, mass spectrometry, and in vitro and in vivo assays to explore the mechanism regulated by ST6GAL1. Finally, we verified the mechanism by performing immunoprecipitation and immunofluorescence (IF) staining.

Results: ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) expression was negatively correlated with the response to neoadjuvant chemotherapy in patients with CRC and negatively correlated with the sensitivity to IFNG in CRC cell lines. We confirmed that ST6GAL1 overexpression inhibited the infiltration of effector T cells, the levels of IFNG produced by CD8⁺ T cells and CD4⁺ T cells decreased, and the levels of granzyme B produced by effector cells decreased in animal models. The results of in vitro assays and phosphorylation chip detection revealed that ST6GAL1 inhibited IFNG receptor 1 (IFNGR1) phosphorylation, thus decreasing the activation of the JAK1/STAT1 signaling pathway. Through immunoprecipitation assays and mass spectrometry, we found that ST6GAL1 can sialylate BICD cargo adaptor 2 (BICD2), thereby affecting the interaction between BICD2 and IFNGR1 to ultimately inhibit the phosphorylation of IFNGR1 and promote immune escape.

Conclusions: Our results confirmed that ST6GAL1 decreases the sensitivity of tumor cells to IFNG. This study describes a novel mechanism by which ST6GAL1 promotes the immune escape and malignant progression of CRC.

Metastasis, the leading cause of cancer-related mortality, is a complex process involving tumor cell detachment from the primary site, survival and dissemination through the circulation, and colonization of distant organs. At each stage, tumor cells face adaptive pressures from successive biological and biomechanical challenges in the local microenvironment, which collectively shape their progression. Traditional in vitro models often fail to replicate these dynamics, while animal models are limited by species differences and restricted real-time monitoring. Microphysiological systems (MPS) have emerged as powerful tools to address these limitations, delivering physiologically relevant cues and precise experimental control to recapitulate step-specific metastatic contexts. This review outlines recent advances in MPS designs for modeling critical hallmarks of metastasis, beginning with matrix interactions, stromal cells, and mechanical forces from the tumor microenvironment that drive epithelial-mesenchymal transition and invasion. The discussion then transitions to MPS that reproduce vascular physiology during intravasation, circulation, and extravasation, and concludes with organ-specific environments for studying colonization and organotropic behavior in the final stages of metastasis. Additionally, common MPS configurations, categorized into horizontal and vertical compartmental arrangements, and strategies for integrating vascularization are explored. Together, these advances highlight the potential of MPS in elucidating metastatic mechanisms and advancing targeted therapies.

Objective: This study aimed to investigate the synergistic antitumor effects and immunoregulatory functions of the SUMOylation inhibitor TAK-981 in combination with the chemotherapeutic agent doxorubicin (DOX) in triple-negative breast cancer (TNBC), as well as to evaluate the safety of this combination strategy, particularly its mitigating effect on DOX-induced cardiotoxicity.

Methods: In vitro experiments were conducted to assess the effects of TAK-981 and DOX, both alone and in combination, on the type I interferon (IFN I) signaling pathway, cell proliferation, and apoptosis in TNBC cells. Mechanistic studies were performed to explore their impact on the IFN I/JAK1/STAT1 axis and the expression of the downstream NKG2D ligand NKG2DL (ULBP2). In vivo animal models were used to evaluate the antitumor efficacy of the combination therapy, its effect on natural killer (NK) cell activity, systemic toxicity, with a focus on its cardioprotective effects.

Results: TAK-981 activated IFN I signaling, and DOX further enhanced IFN I pathway activity. The two drugs demonstrated a synergistic effect, significantly inducing apoptosis and inhibiting proliferation in TNBC cells. Mechanistically, the TAK-981 and DOX combination targeted the IFN I/JAK1/STAT1 signaling axis, downregulating the expression of the NKG2D ligand (ULBP2) through suppression of the NF-κB pathway. In vivo experiments confirmed that the combination therapy effectively inhibited tumor growth, enhanced NK cell activity, and did not increase systemic toxicity. Notably, TAK-981 significantly alleviated DOX-induced cardiotoxicity, improved cardiac function, and reduced fibrosis.

Conclusion: The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment.

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.