Corrigendum: The synergistic effects of pyrotinib combined with adriamycin on HER2-positive breast cancer

Frontiers in Oncology · 2025-03-18

Corrigendum: The Synergistic Effects of Pyrotinib Combined With Adriamycin on HER2-Positive Breast CancerChaokun Wang1, Shuzhen Deng2, Jing Chen1, Xiangyun Xu1, Xiaochen Hu1, Dejiu Kong1, Gaofeng Liang2, Xiang Yuan1, Yuanpei Li3*, Xinshuai Wang1*1 Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.2 Medical College, Henan University of Science and Technology, Luoyang, China.3 Department of Internal Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA* Correspondence: Xinshuai Wang; E-mail: xshuaiw@haust.edu.cn; Yuanpei Li; E-mail: lypli@ucdavis.eduKeywords: HER2 positive breast neoplasm; pyrotinib; adriamycin; synergistic; AktCorrigendum on: full citation of the original version of the article. Error in Figure/TableIn the published article, there was an error in Figure 3 as published. Due to the large number of photos taken, careless naming errors led to the accidental reuse of some images. The corrected Figure 3 and its caption **[ Figure 3. Effects of PYR and ADM on cell invasion.] appear below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Targeted O-GlcNAcylation of CK2α Triggers Its Ubiquitin-Proteasome Degradation and Alters Downstream Phosphorylation

ACS Chemical Biology · 2025-06-16 · 3 citations

O-Linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is an important post-translational modification (PTM), yet dissecting its protein-specific functions has remained challenging. Here, we applied our previously reported chemical biology tool, the O-GlcNAcylation Targeting Chimera (OGTAC), to specifically induce O-GlcNAcylation of the casein kinase II subunit α (CK2α) at Ser347 in living cells. We found that this targeted O-GlcNAcylation destabilized CK2α through ubiquitin-proteasome degradation and enhanced its interaction with cereblon (CRBN). Overexpression and knockdown experiments also indicated CK2α as a substrate of the Cullin-RING E3 ubiquitin ligase 4-CRBN (CRL4CRBN) E3 ligase complex. Furthermore, the OGTAC-induced O-GlcNAcylation of CK2α reprogrammed phosphorylation of Akt and PFKP. These findings reveal that a single O-GlcNAc modification can serve as a molecular switch, controlling the protein stability and downstream phosphorylation of CK2α. More broadly, our results highlight the profound utility of the OGTAC-mediated O-GlcNAcylation to interrogate its cellular functions with specificity, overcoming limitations inherent to prior global perturbation methods.

Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer

Cancers · 2025-09-30

BACKGROUND: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. METHODS: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. RESULTS: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. CONCLUSIONS: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.

Ligand-Directed Self-Assembling Chimeras for Targeted Protein O-GlcNAcylation

ACS Chemical Biology · 2025-12-05 · 1 citations

Precise control of protein-specific O-GlcNAcylation in cells remains a major challenge. Chemically induced proximity (CIP) offers a promising path forward, but its application to targeted protein O-GlcNAcylation has been limited by the lack of ligands that can bind the O-GlcNAc transferase (OGT) without inhibiting its catalytic function. Here, we repurpose a potent OGT inhibitor into a noninhibitory covalent probe using ligand-directed release chemistry (LDR). The resulting ligands covalently label OGT while preserving its enzymatic activity. Building on this scaffold, we developed a self-assembling O-GlcNAcylation Targeting Chimera (OGTAC) that recruits OGT to its native substrate casein kinase IIα (CK2α) in living cells, selectively elevating CK2α O-GlcNAcylation without affecting global modification levels. This new class of self-assembling chimeras covalently engages OGT to induce protein-specific O-GlcNAcylation, offering a versatile platform for dissecting and controlling this essential modification in living cells. Our findings open the door to next-generation OGTACs and related therapeutic strategies for the targeted modulation of the O-GlcNAc signaling.

Multifunctional and Scalable Nanoparticles for Bimodal Image-Guided Phototherapy in Bladder Cancer Treatment

Nano-Micro Letters · 2025-04-18 · 13 citations

Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine. Here, we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs) as a bimodal system for image-guided phototherapy in bladder cancer treatment. PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation, but also exhibit potent autophagy blockage, effectively inducing bladder cancer cell death. Furthermore, PPBC LNPs possess remarkable photoacoustic (PA) and fluorescence (FL) imaging capabilities, enabling imaging with high-resolution, deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy. Specifically, PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy, while FL imaging confirms their prolonged retention at the tumor site for up to 6 days. PPBC LNPs significantly suppress bladder tumor growth, with several tumors completely ablated following just two doses of the nanoparticles and laser treatment. Additionally, PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility, stability, and scalability, showing potential for clinical translation. This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.

Immunomodulatory nanoplatforms with multiple mechanisms of action in cancer treatment

Nanomedicine · 2025-05-07 · 1 citations

Cancer immunotherapies have transformed oncology by utilizing the immune system to target malignancies; however, limitations in efficacy and potential side effects remain significant challenges. Nanoparticles have shown promise in enhancing drug delivery and improving immune activation, with the potential for numerous modifications to tailor them for specific environments or targets. Integrating nanoplatforms offers a promising avenue to overcome these hurdles, enhancing treatment outcomes and reducing adverse effects. By improving drug delivery, targeting, and immune modulation, nanoplatforms can unlock the full potential of cancer immunotherapy. This review explores the role of nanoplatforms in addressing these limitations and enhancing cancer immunotherapy outcomes, examining various types of nanoplatforms. Understanding the mechanisms of immunomodulation through nanoplatform deliveries is crucial. We discuss how these nanoplatforms interact with the tumor microenvironment, modulate tumor-associated macrophages and regulatory T cells, activate immune cells directly, enhance antigen presentation, and promote immunological memory. Further benefits include combination approaches integrating nanoplatforms with chemotherapy, radiotherapy, and phototherapy. Immunotherapy is a relatively new approach, but numerous clinical studies already utilize nanoplatform-based immunotherapies with promising results. This review aims to provide insights into the potential of nanoplatforms to enhance cancer immunotherapy and pave the way for more effective and personalized treatment strategies.

The tumor immune microenvironment: implications for cancer immunotherapy, treatment strategies, and monitoring approaches

Frontiers in Immunology · 2025-09-22 · 12 citations

The tumor immune microenvironment (TIME) plays a pivotal role in cancer progression, detection, and response to cancer treatments. Current knowledge of the diverse and dynamic cellular components of the TIME underscores how the immune landscape evolves in response to immunotherapy. This review highlights the importance of understanding the TIME for advancing cancer immunotherapy by integrating insights from basic biology and clinical practice with recent advances in science and technology, paving the way for more personalized cancer therapies through modern medical innovations. The cellular and molecular compositions of the TIME and the cellular interactions will be explored. Next, we summarize how the TIME is shaped by immune activation and suppression through various mechanisms of action. Immunotherapies designed to enhance host immune function are discussed in detail to visualize and quantify cellular dynamics within the TIME once treated with immunotherapy. In particular, the integration of artificial intelligence (AI) has significantly enhanced early cancer detection and diagnostics by analyzing patient samples with greater precision. The topics are structured to explore core principles, immune activation and suppression, imaging methods, current and emerging therapies, and the broader influence of the TIME on diagnosis, monitoring, and treatment strategies.

A phase I first-in-human clinical trial with PLZ4-coated paclitaxel-loaded micelles (PPM) in therapy-resistant non-muscle-invasive bladder cancer (NMIBC).

Journal of Clinical Oncology · 2025-02-10 · 1 citations

806 Background: Approximately 75% of patients with non-muscle invasive bladder cancer (NMIBC) treated with transurethral resection (TUR) followed by intravesical Bacillus Calmette-Guérin (BCG) experience cancer recurrence. When BCG-unresponsive, most patients continue to have recurrences even with newly approved therapies and nearly 30% progress to invasive stages. We developed a first-in-class bladder cancer-specific nanotherapeutic, PPM, which is administered intravesically. Our preclinical data has demonstrated PPM can selectively target bladder cancer cells and deliver paclitaxel payload into these cancer cells following intravesical or intravenous administration. Methods: This is a 3+3 first-in-human dose escalation trial. Eligible patients must have pathologically confirmed NMIBC, be unresponsive to intravesical BCG therapy (with or without cytotoxic chemotherapy), possess adequate vital organ function, and consent to cystoscopy with TUR for response evaluation. PPM is administered via intravesical instillation once weekly for six weeks. The trial features three dose levels, with paclitaxel doses of 25 mg, 50 mg, and 75 mg. The primary endpoints include safety and the recommended Phase II dose; secondary endpoints encompass response rate, duration of response, systemic drug absorption, and molecular correlative studies. Patients will be followed at 3 month intervals for 2 years or until disease progression. Results: To date, three patients with pathologically confirmed NMIBC have completed a total of 18 treatments at the first dose level without any PPM-related adverse events: one patient was unresponsive to BCG and intravesical mitomycin therapy, while the other two had BCG-unresponsive disease. Two out of the three patients achieved ongoing complete remission for over six and nine months, respectively. The third patient demonstrated persistent disease, but no progression was noted. Enrollment for Dose Level 2 is currently open. Conclusions: PPM has demonstrated promising clinical activity without toxicity at the first dose level in patients with BCG-unresponsive NMIBC. Data at other dose levels will be presented at the meeting (ClinicalTrials.gov identifier: NCT05519241). Clinical trial information: NCT05519241 .

Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy

Small Science · 2025-04-11 · 13 citations

Cancer is a daunting global health problem with a steadily rising incidence. Despite the wide arsenal of current anticancer therapies, challenges such as drug resistance, tumor heterogeneity, poor targeting, and severe side effects often lead to suboptimal efficacy and poor patient outcomes, highlighting the need for innovative therapies. Autophagy modulation has emerged as an attractive approach to complement existing therapies. The dual role of autophagy in cancer promotion and suppression has inspired the development of new drugs and therapeutic strategies focusing on both inhibition and induction. Despite the promising results of current autophagy modulators in preclinical studies, challenges such as the lack of selectivity and potency, toxicity, poor pharmacokinetics, and inadequate tumor targeting continue to limit their successful clinical translation. Many of these challenges could be overcome using nanomedicine. This review explores recent advancements in nanomedicine strategies for autophagy modulation. Successful combination strategies leveraging nanoparticles and autophagy modulators in synergy with chemotherapy, immunotherapy, phototherapy, gene therapy, and other modalities are presented. Additionally, nanomaterials with intrinsic autophagy-modulating capabilities, such as self-assembling autophagy inhibitors, are discussed. Finally, limitations of autophagy modulators currently in clinical trials are discussed, and future perspectives on designing nanomedicine for successful clinical implementation are explored.

Designing Programmable Peptide Nucleic Acid‐based Nanovaccines for Anticancer Immune Activation

Small · 2025-11-07 · 1 citations

Abstract Targeted delivery of antigens and adjuvants to the immune cells without eliciting uncontrolled inflammation is a major challenge in cancer vaccine development. Here, a highly versatile and programmable peptide nucleic acid (PNA)‐based vaccine nanoplatform (PVN) is reported to elicit a robust anti‐tumor immune response against B16‐OVA syngeneic melanoma model. The PVN is built on an 11‐mer PNA scaffold, enabling efficient “one‐pot” loading of a PNA‐modified ovalbumin antigenic peptide (SIINFEKL), CpG adjuvant, and a PNA‐derivatized LLP2A ligand (an immune cell and melanoma cell targeting ligand). Super‐resolution fluorescence imaging reveals the spatial arrangement of OVA 8 within LP 10‐12 [ OVA 8 /CpG/LLP2A ], while circular dichroism spectroscopy confirmsparalleled binding of complementary PNA strands in LP 11 [ OVA 8 /CpG/LLP2A ]. LLP2A displayed on PVNs target activated α4β1 integrin expressed by immune and melanoma cells, boosting antigen presentation by dendritic cells and eliciting strong CD8+T cell and natural killer cell responses. This amplified antitumor immune response leads to significant tumor regression and prolonged survival of mice bearing syngeneic B16‐OVA melanoma. The modular nature and versatility of PVN allow convenient one‐pot assembling of peptide antigens, immunomodulators, immune cell and tumor cell targeting ligands, making it practical for the custom design and preparation of personalized cancer vaccines.