Cancer gene therapy最新文献

The tumor niche promotes immune tolerance, enabling malignant cells to evade surveillance. Mesenchymal stem cells (MSCs) have multipotential differentiation capacity and provide a niche for bone marrow homeostasis. MSCs home to tumor tissues, where they can differentiate into Cancer-associated fibroblasts (CAFs). Within the tumor microenvironment, MSCs drive tumor progression by fostering immune suppression, secreting pro-tumorigenic cytokines, and, in some contexts, maintaining dormancy for later relapse. In this study, we engineered MSCs to deliver the immuno-stimulatory TNF superfamily ligand LIGHT (MSC-L). We found that MSC-L simultaneously primed immune responses against both tumor cells and CAFs. This effect relies on the LIGHT-mediated activation of naïve T cells in draining lymph nodes, which subsequently infiltrate the tumor. The recruited T cells eradicate CAFs, thereby remodeling the immunosuppressive niche and harnessing otherwise immune tolerance antigen loss variants. Our findings underscore the critical role of niche reprogramming in tumor control and demonstrate a novel strategy for co-targeting tumor cells and CAFs, even in immune resistant settings. This approach provides a promising foundation for clinical translation.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world, with therapy resistance posing a substantial obstacle to enhancing patient outcomes. Cancer-associated fibroblasts (CAFs), the predominant stromal cells within the tumor microenvironment (TME), have been identified as pivotal contributors to HCC progression and therapeutic resistance. CAFs have direct or indirect interactions with cancer cells, leading to immune evasion and drug resistance. This review mostly concentrates on the role of CAFs in HCC, particularly how CAFs influence chemotherapy, targeted therapy, and immunotherapy. Additionally, it explores synergistic therapeutic strategies targeting CAFs. It has been found that targeting CAFs or disrupting their interactions with other cells offers promising avenues for dealing with drug resistance and improving the effectiveness of therapies in HCC.

Non-small cell lung cancer (NSCLC) frequently metastasizes to the brain in approximately 20-40% of cases. Mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) are common in NSCLC, with the KRAS^G12C variant accounting for approximately 40% of KRAS-mutant cases. Up to 40% of NSCLC patients harboring the KRAS^G12C mutation develop brain metastases during follow-up, and a substantial proportion present with brain metastases at diagnosis. While KRAS^G12C inhibitors such as sotorasib and adagrasib are approved therapies, most patients with KRAS^G12C mutant NSCLC experience disease progression within 5 to 6 months. Emerging KRAS^G12Cinhibitors, such as adagrasib, RMC-6236, and olomorasib, show intracranial activity in KRAS^G12C mutant NSCLC brain metastases, but adaptive resistance limits their effectiveness as monotherapies. This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRAS^G12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRAS^G12C inhibitors and multimodal therapies.

Gemcitabine-based chemotherapy remains the standard first-line treatment for cholangiocarcinoma (CCA), but acquired resistance presents a significant clinical challenge. Synthetic lethality approaches targeting double-strand break repair (DSBR) pathways offer promising therapeutic opportunities. Ataxia-telangiectasia mutated (ATM) kinase, a central regulator of homologous recombination (HR) and non-homologous end joining (NHEJ), is critical for maintaining genomic integrity following DNA damage. Here, we demonstrate that combining the ATM inhibitor AZD0156 with DNA-damaging agents (cisplatin or photon irradiation) significantly enhances cytotoxicity in gemcitabine-resistant intrahepatic CCA sublines (GR-iCCAs) while sparing gemcitabine-sensitive parental cells. This selective sensitization manifests in impaired colony formation, increased apoptosis, and persistent γ-H2AX nuclear accumulation. The magnitude of AZD0156 sensitization in GR cells substantially exceeds additive expectations, strongly suggesting synergistic interaction. Genetic ATM depletion in GR-iCCAs under genotoxic stress recapitulated these effects, confirming on-target specificity. Mechanistically, GR-iCCAs exhibit significantly reduced DNA ligase I (LIG1) expression, a critical component of the alternative NHEJ (alt-NHEJ) repair pathway, particularly under DNA damage conditions. Genetic restoration of LIG1 expression reversed AZD0156 sensitivity, establishing LIG1 deficiency as a key determinant modulating DNA repair pathway dependency. In xenograft models, AZD0156 combined with cisplatin substantially suppressed tumor growth compared to monotherapy, with acceptable tolerability profiles. These findings identify ATM inhibition as a promising strategy to overcome gemcitabine resistance in CCA, particularly in tumors with compromised alt-NHEJ repair capacity, providing a mechanistic rationale for clinical development of this combination therapy.

Similar to other malignancies, multiple myeloma (MM) has acquired several functional capabilities known as "Hallmarks of cancer", and one of them is the deregulation of cell metabolism, especially glucose metabolism. Our current study focuses on the role of Chromosome 1 Open Reading Frame 35(C1orf35) in the glucose metabolism of MM cells. We found that the expression of C1orf35 was negative correlated with the overall survival of MM patients, MM cell lines with high C1orf35 expression not only had a faster proliferation rate but also higher levels of both aerobic glycolysis and oxidative phosphorylation (OXPHOS). Mechanistic studies revealed that C1orf35 promoted aerobic glycolysis through the c-MYC/PKM2 pathway and interacted with Leucine-Rich PPR Motif-Containing Protein (LRPPRC) to enhance OXPHOS. Moreover, treating MM cells with Gossypol Acetic Acid (GAA), a small molecule inhibitor specifically targeting LRPPRC, unexpectedly led to the degradation of C1orf35 protein and an "energy crisis" in these cells. Finally, we confirmed C1orf35 is on the upstream of PI3K/AKT/mTOR pathway, thus C1orf35 may play a pivotal role in anabolic metabolism. Our study uncovers a "C1orf35-driven" energy metabolism model in MM cells, providing new insights into the pathogenesis of MM and a potential novel target for the treatment of cancer cells with a high"C1orf35-driven" anabolic metabolism. Schematic diagram of C1orf35 simultaneously promotes glycolysis and OXPHOS.

CRISPR/Cas9 represents a transformative advancement in precision therapies, offering the promise of more effective and targeted treatment options. However, there are still limitations (including off-target editing as well as unsatisfied delivery tool) which obstruct the wide application of CRISPR/Cas9. Here, an endogenic artificial extracellular vesicles (EVs) system is engineered for effective delivery of Cas9 ribonucleoprotein (RNP). We demonstrated that the endogenic Cas9 RNP were sorted by the Lamp2b and delivered by the artificial EVs, which could markedly inhibit the growth of cervical cancer cells by inducing cell apoptosis. Moreover, artificial endogenic EVs^RNP (Cas9-Mcl1) could result in remarkable antitumor effects in animal models of cervical cancer through suppressing Mcl1 expression. Our findings indicate that the artificial EVs delivery strategy could deliver Cas9 RNP effectively to inhibit cancer progression, which might be a promising treatment.

Angiogenesis constitutes a critical rate-limiting determinant of tumor progression in breast cancer (BC). Resistance to conventional anti-angiogenic therapies in BC highlights an unmet need to identify upstream molecular regulators coordinating malignant cell plasticity and vascular remodeling. Lemur tail kinase 3 (LMTK3) is a well-established oncogenic kinase; however, its specific role within the tumor angiogenic microenvironment remains undefined. Here, we identify LMTK3 as a context-dependent driver of angiogenesis through a mesenchymal-epithelial transition (MET) program. By integrating single-cell RNA sequencing with functional validation, we uncover a 'Simpson's paradox' (where a correlation present in different groups disappears or reverses when combined): In mesenchymal-like triple-negative breast cancer (TNBC), LMTK3 promotes a pro-angiogenic, 'partial EMT' (p-EMT) state characterized by sustained ERK signaling and elevated secretion of angiogenic factors, including angiogenin. Conversely, in luminal-like cells, LMTK3 enforces a hyperepithelialized state that suppresses angiogenic phenotypes. Consequently, LMTK3 emerges as a central regulator of angiogenic plasticity, and its targeted inhibition offers a promising strategy to abrogate the pro-angiogenic p-EMT state and promote vascular normalization in TNBC.