Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter\'s tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

The resistance of cancer cells to treatment significantly impedes the success of therapy, leading to the recurrence of various types of cancers. Understanding the specific mechanisms of therapy resistance may offer novel approaches for alleviating drug resistance in cancer. Recent research has shown a reciprocal relationship between circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification, and their interaction can affect the resistance and sensitivity of cancer therapy. This review aims to summarize the latest developments in the m6A modification of circRNAs and their importance in regulating therapy resistance in cancer. Furthermore, we explore their mutual interaction and exact mechanisms and provide insights into potential future approaches for reversing cancer resistance.

Neutrophil extracellular traps (NETs) are web-like structures composed of cytoplasmic contents, DNA chromatin and various granular proteins released by neutrophils in response to viruses, bacteria, immune complexes and cytokines. Studies have shown that NETs can promote the occurrence, development and metastasis of tumors. In this paper, the mechanism underlying the formation and degradation of NETs and the malignant biological behaviors of NETs, such as the promotion of tumor cell proliferation, epithelial mesenchymal transition, extracellular matrix remodeling, angiogenesis, immune evasion and tumor-related thrombosis, are described in detail. NETs are being increasingly studied as therapeutic targets for tumors. We have summarized strategies for targeting NETs or interfering with NET-cancer cell interactions and explored the potential application value of NETs as biomarkers in cancer diagnosis and treatment, as well as the relationship between NETs and therapeutic resistance.

The leading cause of cancer deaths worldwide is attributed to non-small cell lung cancer (NSCLC), necessitating a continual focus on improving the diagnosis and treatment of this disease. In this review, the latest breakthroughs and emerging trends in managing NSCLC are highlighted. Major advancements in diagnostic methods, including better imaging technologies and the utilization of molecular biomarkers, are discussed. These advancements have greatly enhanced early detection and personalized treatment plans. Significant improvements in patient outcomes have been achieved by new targeted therapies and immunotherapies, providing new hope for individuals with advanced NSCLC. This review discusses the persistent challenges in accessing advanced treatments and their associated costs despite recent progress. Promising research into new therapies, such as CAR-T cell therapy and oncolytic viruses, which could further revolutionize NSCLC treatment, is also highlighted. This review aims to inform and inspire continued efforts to improve outcomes for NSCLC patients globally, by offering a comprehensive overview of the current state of NSCLC treatment and future possibilities.

Obesity is a multifaceted metabolic disorder characterized by excessive accumulation of adipose tissue. It is a well-established risk factor for the development and progression of breast cancer. Adipose tissue, which was once regarded solely as a passive energy storage depot, is now acknowledged as an active endocrine organ producing a plethora of bioactive molecules known as adipokines that contribute to the elevation of proinflammatory cytokines and estrogen production due to enhanced aromatase activity. In the context of breast cancer, the crosstalk between adipocytes and cancer cells within the adipose microenvironment exerts profound effects on tumor initiation, progression, and therapeutic resistance. Moreover, adipocytes can engage in direct interactions with breast cancer cells through physical contact and paracrine signaling, thereby facilitating cancer cell survival and invasion. This review endeavors to summarize the current understanding of the intricate interplay between adipocyte-associated factors and breast cancer progression. Furthermore, by discussing the different aspects of breast cancer that can be adversely affected by obesity, this review aims to shed light on potential avenues for new and novel therapeutic interventions.

Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.

Inhibitors of Bruton\'s tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.

MicroRNAs (miRNAs) have emerged as crucial regulators of gene expression, playing pivotal roles in various biological processes, including cancer development and progression. Among them, miR-125b has garnered significant attention due to its multifaceted functional roles in human hepatocellular carcinoma (HCC). Extensive research has revealed that miR-125b plays a dual role in HCC, acting as both a tumor suppressor and an oncogene depending on the context. As a tumor suppressor, miR-125b exerts its inhibitory effects on HCC by targeting key oncogenic pathways and genes involved in cell proliferation, migration, invasion, and angiogenesis. Its downregulation in HCC is frequently observed and correlates with aggressive tumor characteristics and poor prognosis. Conversely, miR-125b can also function as an oncogene in specific HCC subtypes or under certain conditions. It has been shown to promote HCC growth, metastasis, and therapeutic resistance by targeting tumor suppressor genes, modulating the epithelial-mesenchymal transition (EMT) process, and enhancing cancer stem cell-like properties. The upregulation of miR-125b in HCC has been associated with advanced disease stages and unfavorable clinical outcomes. Furthermore, the dysregulation of miR-125b expression in HCC is influenced by a complex network of regulatory mechanisms. Understanding these regulatory mechanisms is crucial for deciphering the precise functional roles of miR-125b in HCC and exploring its potential as a diagnostic biomarker or therapeutic target. In the current review study, we comprehensively elucidated the diverse functional roles of miR-125b in HCC, providing a comprehensive overview of its regulatory mechanisms and impact on key cellular processes involved in HCC progression.

Non-small cell lung cancer (NSCLC) is a malignant cancer that with high incidence, recurrence, and mortality rates in human beings, posing significant threats to human health. Moreover, effective early diagnosis of NSCLC remains limited primarily by the lack of accurate biomarkers. Therefore, there is an urgent need to understand the mechanisms underlying NSCLC pathogenesis and treatment failure. Methyltransferase-like 3 (METTL3) is a prototypical member of a family of which its members transfer methyl groups. It has been implicated in modulating the pathogenesis of NSCLC, as well as conferring resistance to NSCLC therapeutics. The targeting of METTL3 for NSCLC treatment has been reported. However, the relationship between METTL3 and NSCLC remains to be demonstrated. In this review, we discuss relevant interrelationships by summarising the studies on METTL3 in NSCLC pathogenesis, therapeutic resistance, and clinical applications. Current research suggests that the upregulation of METTL3 expression propels the tumorigenesis, progression, and treatment resistance of NSCLC. Therefore, we propose that METTL3 is an excellent candidate biomarker for NSCLC diagnosis and prognosis. Therapeutic targeting of METTL3 has significant potential for NSCLC treatment. This review provides a summary of the association between METTL3 and NSCLC, which would be a valuable reference for both basic and clinical research.

Metronomic chemotherapy (MCT), characterized by the continuous administration of chemotherapeutics at a lower dose without prolonged drug-free periods, has garnered significant attention over the last 2 decades. Extensive evidence from both pre-clinical and clinical settings indicates that MCT induces distinct biological effects than the standard Maximum Tolerated Dose (MTD) chemotherapy. The low toxicity profile, reduced likelihood of inducing acquired therapeutic resistance, and low cost of MCT render it an attractive chemotherapeutic regimen option. One of the most prominent aspects of MCT is its anti-angiogenesis effects. It has been shown to stimulate the expression of anti-angiogenic molecules, thereby inhibiting angiogenesis. In addition, MCT has been shown to decrease the regulatory T-cell population and promote anti-tumor immune response through inducing dendritic cell maturation and increasing the number of cytotoxic T-cells. Combination therapies utilizing MCT along with oncolytic virotherapy, radiotherapy or other chemotherapeutic regimens have been studied extensively. This review provides an overview of the current status of MCT research and the established mechanisms of action of MCT treatment and also offers insights into potential avenues of development for MCT in the future.