Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 28, 2023

Abstract Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel LAG-3 drugs have also been approved clinical application. With the widespread use of drug, we must deeply analyze dilemma agents seek a breakthrough treatment prospect. Over past decades, these demonstrated dramatic efficacy, especially patients with melanoma non-small cell lung cancer (NSCLC). Nonetheless, field broad concept solid tumours, non-specific indications, inseparable immune response side effects, unconfirmed progressive disease, complex regulatory networks resistance are four barriers that limit its Fortunately, successful trials ICB combination therapies, advent era oncolytic virus gene editing, technical mRNA vaccines nano-delivery systems made remarkable breakthroughs currently. In this review, enumerate mechanisms each checkpoint targets, associations between tumour mutation burden, key or signalling pathways, specific evidence efficacy classical targets new among different types put forward dialectical thoughts on drug safety. Finally, discuss importance accurate triage based recent advances predictive biomarkers diagnostic testing techniques.

Язык: Английский

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Emerging Sonodynamic Therapy‐Based Nanomedicines for Cancer Immunotherapy

Advanced Science, Год журнала: 2022, Номер 10(2)

Опубликована: Ноя. 27, 2022

Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected as a highly efficient paradigm. However, these treatments have significant limitations, either causing damage of the immune system or limited superficial tumors. Sonodynamic therapy (SDT) ICD promote without affecting because its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still reactive oxygen species yield complex tumor microenvironment. Recently, some emerging SDT-based nanomedicines made numerous attractive encouraging achievements in field cancer due high immunotherapeutic efficiency. this cross-cutting research far from being widely explored huge professional barriers. Herein, characteristics microenvironment mechanisms are firstly systematically summarized. Subsequently, therapeutic mechanism fully summarized, advantages limitations discussed. The representative advances for further highlighted. Finally, application prospects challenges future clinical translation

Язык: Английский

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New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects

Drug Resistance Updates, Год журнала: 2022, Номер 64, С. 100849 - 100849

Опубликована: Июнь 30, 2022

Язык: Английский

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HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1

Cell Reports, Год журнала: 2023, Номер 42(8), С. 112945 - 112945

Опубликована: Авг. 1, 2023

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which under hypoxia, HIF-1α is main driver of hypoxia-induced Mechanistically, HIF-1α-induced lactate contributes to pH-dependent manner parallel classical SLC7A11 and FSP1 systems. addition, also enhances transcription SLC1A1, an important glutamate transporter, cystine uptake promote support role hypoxia resistance, silencing sensitizes mouse inducers. conclusion, our results reveal by drives identify alleviation induction as promising therapeutic strategy for tumors.

Язык: Английский

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Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

ACS Nano, Год журнала: 2023, Номер 17(5), С. 4667 - 4687

Опубликована: Март 2, 2023

The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals tumor cells are able to avoid various tolerance mechanisms by alleviating the intracellular environment. Herein we reported nanoreactor Cu2-xSe that enabled conversion Cu elements between Cu+ Cu2+ generation O2 consumption GSH content. Furthermore, enhance catalytic ferroptosis-inducing activities nanoreactors, agonist Erastin was loaded ZIF-8 coating surface up-regulate expression NOX4 protein, increase H2O2 content, catalyze produce activate ferroptosis. In addition, nanoreactors were simultaneously functionalized with PEG polymer folic acid molecules, which ensured vivo blood circulation tumor-specific uptake. vitro experiments demonstrated self-supplying can amplify ability generate consume via interconversion Cu2+, impair GPX4/GSH pathway HIF-1α protein expression. At same time, environment, miR301, gene secreted exosomes decreased, ultimately affected phenotype polarization TAMs increased content IFN γ CD8+ T cells, further promoted induced Erastin-loaded nanoreactors. This combined therapeutic strategy activating immune response provides potential application.

Язык: Английский

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Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Cancers, Год журнала: 2022, Номер 14(19), С. 4562 - 4562

Опубликована: Сен. 20, 2022

Lung cancer is one of the leading causes cancer-related deaths worldwide with a 5-year survival rate less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains major obstacle effectiveness long-term treatment, eventually insensitivity, poor progression-free survival, disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations microenvironment, several other cellular molecular alterations. A better understanding these crucial for targeting factors involved resistance, establishing novel antitumor targets, developing strategies resensitize cells towards treatment. In this review, we summarize diverse driving radiotherapy, immunotherapy, promising help overcome resistance.

Язык: Английский

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Hypoxia signaling in cancer: Implications for therapeutic interventions

MedComm, Год журнала: 2023, Номер 4(1)

Опубликована: Янв. 23, 2023

Abstract Hypoxia is a persistent physiological feature of many different solid tumors and key driver malignancy, in recent years, it has been recognized as an important target for cancer therapy. occurs the majority due to poor vascular oxygen supply that not sufficient meet needs rapidly proliferating cells. A hypoxic tumor microenvironment (TME) can reduce effectiveness other therapies, such radiotherapy, chemotherapy, immunotherapy. In this review, we discuss critical role hypoxia development, including metabolism, immunity, angiogenesis. The treatment methods TME are summarized, hypoxia‐targeted therapy improving oxygenation by alleviating itself. Hyperoxia be used improve tissue partial pressure relieve hypoxia. We focus on underlying mechanisms hyperoxia their impact current therapies prospects treatment.

Язык: Английский

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Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 207, С. 115239 - 115239

Опубликована: Март 3, 2024

Язык: Английский

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Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(5), С. e005719 - e005719

Опубликована: Май 1, 2023

Background Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations certain tumor types and patients. The efficacy of depends on antigen-specific CD8 T-cell viability functionality within immunosuppressive microenvironment, where oxygen levels are often low. Hypoxia can reduce fitness several ways T cells mostly excluded from hypoxic regions. Given challenges to achieve durable reduction hypoxia clinic, ameliorating survival effector function condition could improve response immunotherapies. Methods Activated were exposed metformin analyzed by fluorescence-activated cell sorting for proliferation, apoptosis phenotype. In vivo, was administered mice bearing tumors receiving either adoptive therapy with tumor-specific cells, or immune checkpoint inhibitors; growth followed time infiltration, localization normoxic regions assessed flow cytometry immunofluorescence. Tumor oxygenation measured electron paramagnetic resonance pimonidazole staining, respectively. Results We found that antidiabetic drug directly improved hypoxia, both vitro vivo. Metformin rescued murine human hypoxia-induced increased proliferation cytokine production, while blunting upregulation programmed death protein 1 lymphocyte-activation gene 3. This appeared result a reduced production reactive species, due inhibition mitochondrial complex I. Differently what others reported, did not but rather infiltration areas, synergized cyclophosphamide enhance blockade different models. Conclusions study describes novel mechanism action presents promising strategy rejection tumors, which would otherwise be resistant immunotherapy.

Язык: Английский

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Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Июль 18, 2023

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that widely used due to their demonstrated efficacy against tumors favorable safety profiles or tolerability. Nevertheless, resistance continues be one of the most pressing unsolved conundrums in treatment. Hypoxia-inducible factors (HIFs) a family transcription regulate cellular responses hypoxia by activating genes involved various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, apoptosis. Despite this critical function, overexpression HIFs has been observed numerous cancers, leading therapy disease progression. In recent years, much effort poured into developing innovative treatments target HIF pathway. Combining inhibitors with current therapies increase anti-tumor activity diminish is strategy for combating therapeutic resistance. This review focuses on how could applied conjunction treatments, those now being evaluated clinical trials, usher new era therapy.

Язык: Английский

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