Targeting KRAS: from metabolic regulation to cancer treatment

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

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Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and subsequent release DNA (mtDNA), which is anticipated to activate cGAS-STING pathway, thereby augmenting antitumor immune response. However, challenges lie in effectively triggering cancer cells subsequently enhancing activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators cobalt fluoride (CoF2) nanocatalysts for catalytic metalloimmunotherapy. CoF2 a semiconductor structure enzyme-like activity generated substantial amount reactive oxygen species (ROS) under stimulation by endogenous H2O2 exogenous ultrasound. Importantly, discovered that Co-based nanomaterials themselves induce cells. Therefore, initially acted as inducers, caspase-1/GSDMD-dependent via Co2+ ROS, leading mtDNA release. Subsequently, were further utilized STING agonists specifically capable detecting pathway. These cascade events triggered robust response, modulating immunosuppressive tumor microenvironment into an immune-supportive state, providing favorable support therapy. This innovative strategy not only significantly impeded growth primary but also elicited response augment efficacy checkpoint inhibitors preventing distant progression. Overall, this study proposed self-cascade activating amplifying pathway specificity mediated pyroptosis, representing valuable avenue future

Language: Английский

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YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer

Cancer Research, Journal Year: 2024, Volume and Issue: 84(22), P. 3728 - 3742

Published: Aug. 13, 2024

Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically "cold" tumor microenvironment and considered a promising target enhance immunotherapy response. In this study, we aimed reveal mechanisms regulating CAF plasticity identify potential strategies switch CAFs from protumorigenic antitumor phenotypes ICB efficacy in prostate cancer. Integration four single-cell RNA sequencing datasets defined CAFs, RNA-seq, flow cytometry, organoid model demonstrated functions two subtypes. Extracellular matrix-associated (ECM-CAF) promoted collagen deposition cell progression, lymphocyte-associated (Lym-CAF) exhibited an phenotype induced infiltration activation CD8+ T cells. YAP1 activity regulated ECM-CAF phenotype, silencing switching Lym-CAFs. NF-κB p65 was core transcription factor Lym-CAF subset, inhibited nuclear translocation p65. Selective depletion ECM-CAFs vivo T-cell enhanced therapeutic effects anti-PD-1 treatment on Overall, study revealed mechanism identity highlighted strategy for altering subtype suppress growth increase sensitivity ICB. Significance: regulates cancer-associated fibroblast can be targeted that promotes extracellular matrix tumor-suppressive stimulates immunity efficacy.

Language: Английский

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Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion

Biology, Journal Year: 2024, Volume and Issue: 13(5), P. 307 - 307

Published: April 28, 2024

Cancer immune evasion represents a leading hallmark of cancer, posing significant obstacle to the development successful anticancer therapies. However, landscape cancer treatment has significantly evolved, transitioning into era immunotherapy from conventional methods such as surgical resection, radiotherapy, chemotherapy, and targeted drug therapy. Immunotherapy emerged pivotal component in treatment, harnessing body’s system combat offering improved prognostic outcomes for numerous patients. The remarkable success spurred efforts enhance clinical efficacy existing agents strategies. Several immunotherapeutic approaches have received approval treatments, while others are currently preclinical trials. This review explores recent progress unraveling mechanisms evaluates effectiveness diverse strategies, including vaccines, adoptive cell therapy, antibody-based treatments. It encompasses both established treatments those under investigation, providing comprehensive overview through immunological approaches. Additionally, article emphasizes current developments, limitations, challenges immunotherapy. Furthermore, by integrating analyses resistance exploring combination strategies personalized approaches, it offers valuable insights crucial novel

Language: Английский

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M7G-related tumor immunity: novel insights of RNA modification and potential therapeutic targets

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(4), P. 1238 - 1255

Published: Jan. 1, 2024

RNA modifications play a pivotal role in regulating cellular biology by exerting influence over distribution features and molecular functions at the post-transcriptional level.Among these modifications, N7-methylguanosine (m7G) stands out as one of most prevalent.Over recent years, significant attention has been directed towards understanding implications m7G modification.This modification is present diverse molecules, including transfer RNAs, messenger ribosomal other noncoding RNAs.Its regulation occurs through series specific methyltransferases m7G-binding proteins.Notably, implicated various diseases, prominently across multiple cancer types.Earlier studies have elucidated significance context immune within tumor microenvironment.This comprehensive review culminates synthesis findings related to modulation cells infiltration, encompassing T cells, B innate all orchestrated modification.Furthermore, interplay between its regulatory proteins can profoundly affect efficacy adjuvant therapeutics, thereby potentially serving biomarker therapeutic target for combinatory interventions types.

Language: Английский

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Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(6), P. 520 - 536

Published: May 13, 2024

Language: Английский

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Next-generation combination approaches for immune checkpoint therapy

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(12), P. 2186 - 2199

Published: Nov. 25, 2024

Language: Английский

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Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS‐STING Activation for Bidirectional Synergistic Hydrogen‐Immunotherapy

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Abstract The cGAS‐STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid‐phase exfoliation and situ replacement to modulate thereby enhancing for bidirectional synergistic H 2 ‐immunotherapy. obtained MnG can be etched by water, enabling efficient sustained generation gas 2+ . not only activated amplified through release but also regulated glucose metabolism inhibit expression three prime repair exonuclease (TREX2), synergistically injection into tumors resulted a robust immune response, providing favorable support therapy. Consequently, combination with checkpoint blockade therapy significant suppression both primary distant tumors. Furthermore, MnG‐lipiodol dispersion exhibited remarkable efficacy transarterial embolization (TAE)‐gas‐immunotherapy rabbit orthotopic liver model. present study underscores significance employing metal cell strategy enhanced immunotherapy, offering novel approach rational design bioactive materials augment immunotherapeutic effectiveness.

Language: Английский

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Editorial: High Baseline ALT Level Confers Risk of Hepatic Adverse Events During Immune Checkpoint Inhibitors Treatment—A Call for Caution

Alimentary Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

The discovery of immune checkpoint inhibitors (ICIs) is a major breakthrough for the treatment patients with variety malignancies, including hepatocellular carcinoma (HCC). Evidence has accumulated that ICIs can induce remission and prolong survival advanced malignancies. Hence, ICI-based regimens are recommended as first-line systemic therapy [1, 2]. However, increased application ICI treatments raised concerns regarding their hepatotoxicity, especially in HCC [3]. It remains unclear whether ICI-induced hepatic adverse events (AEs) more common than other cancer types. Moreover, risk factors AEs during non-HCC respectively, need to be identified. Recently, Hung et al. compared incidence those malignancies retrospective cohort hepatitis B virus (HBV)-endemic areas [4]. They showed had higher flare HBV reactivation (HBVr) whereas incidences immune-related (irHepatitis) were similar two groups patients. Furthermore, they identified baseline alanine aminotransferase (ALT) concentration exceeding 40 U/L was an independent factor grade 3 or irHepatitis. These results demonstrate susceptibility treatment-associated highlight importance monitoring ALT concentrations nucleos(t)ide analogue (NUC) prophylaxis before initiation treatment. authors did not propose practical model on basis predict irHepatitis large proportion have liver cirrhosis thus impaired function elevated levels. Therefore, hardly used clinical decision-making severe which caused by pre-existing diseases. In contrast, suitable cutoff value would support evaluating probability treatment-induced AEs. Predictive models been developed immunotherapy-related but lacking [5-7]. researchers found increases HBVr this accompanied antiviral [4, 8]. according another study authors, also restore exhausted T-cell immunity, may accelerate loss surface antigen (HBsAg) thereby contribute functional cure chronic [9]. effect anti-HBV immunity appears double-edged, depending balance status NUC employed (Figure 1). Nevertheless, it DNA load HBsAg determine immunity. Thus, mechanisms underpinning double-edged role infection further delineated. Ze-Hua Zhao: writing – original draft. Yu-Chen Fan: conceptualization, review editing, funding acquisition. declare no conflicts interest. This article linked al papers. To view these articles, visit https://doi.org/10.1111/apt.18403 https://doi.org/10.1111/apt.18491. nothing report.

Language: Английский

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Plant-derived Pembrolizumab in conjugation with IL-15Rα-IL-15 complex shows effective anti-tumor activity

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0316790 - e0316790

Published: Jan. 14, 2025

Anti-programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) have proven to be effective in treating various cancers, including colorectal, lung, and melanoma. Despite their clinical success, some patients develop resistance mAbs, requiring co-treatments with radio- or chemotherapy. Interleukin-15 (IL-15) is an immunostimulatory cytokine that promotes immune production proliferation. It has been combined mAbs other immunotherapies improve efficacy reduce side effects. Fusion of anti-PD-1 mAb IL-15 streamlines drug administration management. In this study, we developed a prototype by conjugating the receptor subunit alpha (IL-15Rα) complex C-terminus Pembrolizumab (Pembrolizumab-IL-15Rα-IL15) using plant molecular farming for production. LC-MS revealed presence N -glycans (GnGnXF, GnXF Man9GlcNAc2) on molecule, which may affect receptor-binding avidity. However, ELISA demonstrated comparable binding Pembrolizumab-IL-15Rα-IL15 human PD-1 protein as commercial Pembrolizumab. mouse anti-cancer (3 mg kg -1 ) exhibited slightly improved tumor-growth inhibition, reducing tumor size 94% compared (5 83% reduction, regardless statistically significant difference. conclusion, Pembrolizumab-IL-15Rα-IL-15 was successfully produced shows promise addressing enhancing immunomodulatory effects payload.

Language: Английский

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