Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

Cells, Journal Year: 2024, Volume and Issue: 13(22), P. 1924 - 1924

Published: Nov. 20, 2024

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function contributes failure. However, acidic conditions TME disrupt interaction between cancer cells, driving tumor-infiltrating T cells NK into an inactivated, anergic state. Simultaneously, promotes recruitment activation of immunosuppressive such as myeloid-derived suppressor regulatory (Tregs). Notably, acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor thus acts "protective shield," neutralizing anti-tumor responses transforming pro-tumor allies. Therefore, targeting lactate metabolism has emerged promising strategy overcome this barrier, with approaches including buffer agents neutralize pH inhibitors block production or transport, thereby restoring efficacy TME. Recent discoveries have identified genes involved (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims elucidate molecular mechanisms acidification develop treatments modulate levels enhance outcomes. Additionally, future studies are crucial validate safety pHe-targeted therapies patients. Thus, review explores regulation pHe its potential role improving immunotherapy.

Language: Английский

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PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 4, 2024

Immunotherapy has been developed, which harnesses and enhances the innate powers of immune system to fight disease, particularly cancer. PD-1 (programmed death-1) PD-L1 death ligand-1) are key components in regulation system, context cancer immunotherapy. regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation glycosylation. PROTACs (Proteolysis Targeting Chimeras) a type new drug design technology. They specifically engineered molecules that target specific proteins within cell for degradation. have designed demonstrated their inhibitory activity against PD-1/PD-L1 pathway, showed ability degrade proteins. In this review, we describe how improve efficacy could be novel strategy combine with radiotherapy, chemotherapy immunotherapy patients.

Language: Английский

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Current trends in sensitizing immune checkpoint inhibitors for cancer treatment

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Dec. 26, 2024

Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune blockade (ICB) remains critical challenge, characterized by variable response rates and non-durable benefits. However, growing research into complex intrinsic extrinsic characteristics tumors has advanced our understanding mechanisms behind ICI resistance, potentially improving outcomes. Additionally, robust predictive biomarkers are crucial optimizing patient selection maximizing efficacy ICBs. Recent studies emphasized that multiple rational combination strategies can overcome enhance susceptibility ICIs. These findings not only deepen tumor biology but also reveal unique action sensitizing agents, extending benefits in cancer immunotherapy. In this review, we will explore underlying ICIs, discuss significance microenvironment (TIME) biomarkers, analyze current outline alternative effectiveness including personalized

Language: Английский

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Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 23, 2024

Abstract Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is major cause of cancer-related mortality. Aberrant activation the PI3K/AKT/mTOR signaling pathway common driver NSCLC. Within this study, inhibitory activity (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC demonstrated for first time both in vitro vivo. Mechanistically, it confirmed that targeted suppressed (+)-ABX, resulting induction S G2/M phase arrest, apoptosis, autophagy cells. Additionally, augmentation intracellular ROS levels (+)-ABX revealed, further contributing to inhibition exerting effects on tumor growth. The findings presented study suggest possesses potential serve as lead treatment Graphical abstract

Language: Английский

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Exosomal PD-L1 in cancer and other fields: recent advances and perspectives

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 25, 2024

PD-1/PD-L1 signaling is a key factor of local immunosuppression in the tumor microenvironment. Immune checkpoint inhibitors targeting have achieved tremendous success clinic. However, several types cancer are particularly refractory to anti–PD-1/PD-L1 treatment. Recently, series studies reported that IFN-γ can stimulate cells release exosomal PD-L1 (exoPD-L1), which possesses ability suppress anticancer immune responses and associated with anti-PD-1 response. In this review, we introduce signaling, including so-called ‘reverse signaling’. Furthermore, summarize treatments cancers pay more attention signaling. Additionally, review action mechanisms regulation exoPD-L1. We also function exoPD-L1 as biomarkers. Finally, methods for analyzing quantifying exoPD-L1, therapeutic strategies enhance immunotherapy roles beyond cancer. This comprehensive delves into recent advances all these findings suggest plays an important role both other fields.

Language: Английский

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Recent progress of porphyrin metal-organic frameworks for combined photodynamic therapy and hypoxia-activated chemotherapy

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(93), P. 13641 - 13652

Published: Jan. 1, 2024

Hypoxia limits the phototherapeutic efficacy of porphyrin-based nMOFs; loading with hypoxia-activated drug TPZ enhances combined PDT and chemotherapy effects.

Language: Английский

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Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 10, 2024

In recent years, ICIs have transformed cancer treatment by harnessing the body's immune system to target and destroy cells [1][2][3]. work blocking inhibitory signals that prevent T from attacking tumors, thereby reactivating response against cancer. The most common targets for these therapies are PD-1/PD-L1 CTLA-4 pathways, which critical in regulating responses [4]. By inhibiting drugs like nivolumab, pembrolizumab, ipilimumab shown remarkable efficacy treating cancers such as melanoma, non-small cell lung (NSCLC), renal carcinomaFor example, a PD -1 inhibitor, has been breakthrough of melanoma. large -scale clinical trial involving patients with advanced nivolumab led significant improvement overall survival, approximately 40% surviving more than five years compared less 20% traditional chemotherapy [5]. Pembrolizumab, another non -small (NSCLC). phase III trial, it demonstrated an objective rate around -30% previously treated since incorporated into first -line regimens, improving survival outcomes quality life many [6]. Ipilimumab, CTLA -4 had transformative impact on metastatic It was drug show benefit this difficult -to -treat cancer, increasing median time several months providing new option limited alternatives [7,8]. While range cancers, including melanoma their potential bone tumors remains underexplored. Addressing gap, article also considers strategies tailored enhance ICI specifically tumor casesThese examples clearly illustrate success different types ability revolutionize treatment. underexplored.Addressing cases.These particularly revolutionary were treat, offering long-term remission some patients. However, despite successes, not universally effective. Many do respond treatment, those who may develop resistance over [9]. Additionally, activation can lead severe immune-related adverse events (irAEs), affect various organs require careful management [10]. challenges suboptimal toxicity highlight need refined use ICIs. Personalized approaches, combination therapies, development next-generation improved specificity safety profiles essential maximizing therapeutic treatments.Despite ICIs, is accompanied challenges.One foremost issues variable among individuals experience dramatic long-lasting regression, others at all, phenomenon known primary Even responders, subset acquired time, leading progression after initial period [11].Another challenge occurrence irAEs. These toxicities arise multiple organs, skin, gastrointestinal tract, liver, endocrine [12]. IrAEs mild be life-threatening, necessitating immunosuppressive treatments might diminish anti-tumor [13]. Furthermore, high cost presents barrier access, limiting availability broader patient populationAdditionally, major hurdle. Primary resistance, where start, attributed factors. Tumors low immunogenicity, due lack -specific antigens or suppressive microenvironment rich regulatory (Tregs) myeloid -derived suppressor (MDSCs), effective infiltration [14]. Genetic alterations within cells, mutations interferongamma pathway genes, [15]. Acquired develops initially responsive patients, involve upregulation alternative checkpoint TIM -3 LAG -3, compensate blocked -1/PD -L1 pathways [16]. Tumor adapt losing expression developing mechanisms evade recognition, through antigenpresentation machinery defects [17]. Understanding underlying crucial sets stage later discussion emerging overcome resistance. population [18]. underscore urgent predict response, manage toxicity, reduce costs, optimizing application therapy.ICIs targeting become integral modern therapy [19,20]. PD-1 inhibitors, interaction between its ligand PD-L1 reinvigorating attack [21]. inhibitors substantial carcinoma. Similarly, dampen responses, context [22]. Despite all therapies. Response rates vary significantly, being resistant factors, genetic [23]. Bone osteosarcoma, present unique immunotherapy complex [24]. This explores how approaches could potentially barriers, while outlook they curative portion eventually [25]. limitations ongoing research refine improve rates.The introduction marked advancement therapy, but associated distinct set Unlike chemotherapy-induced toxicities, irAEs result overactivation begins only healthy tissues [26]. almost any organ system, commonly impacted glands [27].Dermatologic rash pruritus, frequent irAEs, often appearing early [28]. Gastrointestinal colitis diarrhea, severe, life-threatening complications if promptly managed [29]. Hepatotoxicity, manifesting elevated liver enzymes hepatitis, concern requires monitoring sometimes cessation [30]. Endocrine thyroiditis, adrenal insufficiency, hypophysitis, hormonal imbalances, hormone replacement therapy. Pulmonary pneumonitis, life-threatening. Cardiovascular neurological though rare, occur pose serious risks.The involves corticosteroids other immunosuppressants mitigate [31]. approach compromise creating delicate balance controlling maintaining benefit. unpredictability nature close monitoring, intervention, selective minimize off-target effects. As continues expand, understanding managing will outcomes.Biomarker-guided represents promising enhancing tailoring characteristics each patient's [32]. Biomarkers expression, mutational burden (TMB), microsatellite instability (MSI) identified predictors For better making factor selection acknowledged factors influence instance, presence microenvironment, Tregs MDSCs, [33]. interferon -gamma sensitivity even levels [34]. Therefore, comprehensive evaluation takes account accurate prediction.Similarly, burden, reflects number tumor's DNA, correlated increased neoantigen formation, system's recognize [35]. Microsatellite instability, condition hypermutability, serves biomarker colorectal [36].By utilizing biomarkers, clinicians accurately identify likely thus outcomes. Currently, there efforts standardize assessment biomarkers. Several professional organizations consortia working towards establishing unified testing methods criteria evaluation. includes standardizing assays used measure TMB, MSI, well defining cut -off values determining positivity [37][38][39].Standardization would reproducibility generalizability -guided strategies. If laboratories clinics inconsistent methods, varying results inaccurate selection. With standardized assessment, reliability -based decisions improve, allowing implementation personalized medicine focused discovering biomarkers refining existing ones, future.Combination emerged powerful strategy [40]. combining modalities, chemotherapy, targeted radiotherapy, possible achieve robust durable [41]. rationale behind combinations lies synergistic effects achieved when complementary involved growth evasion.For radiotherapy induce immunogenic death, increases release enhances subsequent paired [42]. Targeted angiogenesis specific oncogenic modify susceptible immunemediated destruction. simultaneously block checkpoints, tumor.Recent trials showing extended monotherapy [43]. challenges, complexity [44]. continued exploration holds promise adequately alone.Optimizing dosing scheduling minimizing toxicities. Traditional regimens fixed doses schedules individual variability metabolism [45]. Emerging evidence suggests strategies, intermittent dose reductions, maintain reducing risk allow tolerable comorbidities lower tolerance treatment.In addition optimization, adjusting timing administration explored way administering conjunction treatments, intervals taking advantage immunomodulatory [46]. relation circadian rhythms cycles area active research, further optimal results. represent avenues effectiveness therapy.Selective engineering [47]. effective, broad system. To address this, researchers nextgeneration designed precisely sparing tissues.One enhanced affinity tumor-specific altered proteins predominantly expressed microenvironment. reduces minimizes higher without [48].In selectivity, advances protein enabling creation optimized pharmacokinetics pharmacodynamics [49]. engineered longer half-lives, greater stability, controlled activation, dosing. bispecific antibodies two checkpoints combine inhibition immune-stimulating functions increase potency innovations paving safer immunotherapies, hope benefited treatments.Immune modulation aim preserving [50]. One agents excessive cause blunt desired activation. Researchers exploring modulators selectively compromising [51].In pharmacological interventions, modulate effectively. promote immune-regulating extent [52].These still stages hold tolerable, side effects.Effective components inhibitor (ICI) Given systems, detection intervention complications. Routine receiving should include regular assessments symptoms, laboratory tests, imaging studies detect [53]. Early identification allows prompt management, adjustments, temporary discontinuation initiation control inflammation.A multidisciplinary required diverse Involvement specialists, endocrinologists, gastroenterologists, pulmonologists, help [54]. education plays role aware signs symptoms importance reporting them healthcare team. proactive communication earlier interventions outcomes.Long-term essential, late course ended. Continued follow-up ensures delayed appropriately health maintained.By integrating protocols approach, maximize benefits risks, ultimately therapy.In article, we explore aimed biomarker-guided scheduling, summarized Table 1. table provides concise overview key intended outcomes, illustrating both Enhanced ICIs.Maximizing schedules.Minimized designing antigens, reduced irAEs.Balancing suppression corticosteroids, modulators, strategic ICIs.The future overcoming current expanding treatments. offer selectivity [55]. Advances biotechnology antibodies, molecules, novel provide broaden applicability wider currently therapies.In development, ICIsImportantly, positive -effectiveness developed, lines costlier. ensure prescribed benefit, avoiding unnecessary costs -responders. [56]. identifying molecular contribute restore integration practice ensuring receive based characteristics.Another direction sequencing Optimizing evolve, growing interest non-cancer indications, opening frontiers autoimmune diseases chronic infections. Together, shape cornerstone precision oncology.In summary, revolutionized presenting limitations. Ongoing dosing, ICIs.By effectively integrated patients.The hinges collaborative researchers, clinicians, industry leaders. fully realize prioritize mechanisms, precise profiles. Clinicians must adopt training professionals stay informed about latest advancements fostering innovation, collaboration, education, oncology community accessible beneficial act now, refinement shaping treatment.The refinements poised significantly continue aspects biology. promises expand enable safely developments pave paradigms focus disease increasingly rely comprehensive, patient-specific life.

Language: Английский

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Efficacy and safety of ondansetron orally soluble pellicle for preventing moderate- to high-emetic risk chemotherapy-induced nausea and vomiting

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 6, 2025

Ondansetron orally soluble pellicle can serve as an alternative option for preventing nausea and vomiting in patients who receive chemotherapy. However, there is a lack of clinical evidence regarding ondansetron. This study aimed to explore the efficacy safety ondansetron with malignant tumours received chemotherapy drugs moderate-to-high emetic risk. In total, 163 24 mg via pellicles at 30 min before (8 each time three consecutive administrations). The incidence rates days after were recorded. Regarding effect on vomiting, complete response (zero episodes vomiting), major (1–2 minor (3–5 failure (> 5 vomiting) 96.9%, 1.2%, 0%, respectively. rate (complete + rates) was 98.1%. Moreover, 96.3% did not experience nausea, 2.5% experienced mild 1.2% moderate 0.0% severe nausea. (no nausea) 96.3%. Age > 65 years negatively associated regimen involving cisplatin A total 42 (25.8%) adverse events. most common events elevated levels alanine transaminase (6.7%), aspartate (3.7%), fatigue cough (2.5%). shows good antiemetic high

Language: Английский

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Global research trends on biomarkers for cancer immunotherapy: Visualization and bibliometric analysis

Human Vaccines & Immunotherapeutics, Journal Year: 2025, Volume and Issue: 21(1)

Published: Jan. 8, 2025

The global burden of cancer continues to grow, posing a significant public health challenge. Although immunotherapy has shown efficacy, the response rate is not high. Therefore, objective our research was identify latest trends and hotspots on biomarkers from 1993 2023. Data were collected database Web Science core collection. Bibliometric analysis visualization conducted with CiteSpace(6.3.1), VOSviewer (v1.6.20), R-bibliometrix(v4.3.3), Microsoft Excel(2019). A total 2686 literatures retrieved. sheer annual volume publications rapid upward trend since 2015. United States generated most Harvard University ranked as leading institution. biomarker immune checkpoint inhibitors (ICIs) revealed regional differences in-depth explorations should be promoted in developing countries. China become second largest country terms publication, average citation per paper link strength both lower than other mainly concentrated upon following aspects: PD-1/PD-L1, CTLA-4, gene expression, adverse events, mutational (TMB), body mass index (BMI), gut microbiota, cd8(+)/cd4(+) t-cells, blood-related such lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), cytokines. Furthermore, "artificial intelligence" "machine learning" have important hotspot over last 2 y, which will help us useful complex big data provide basis for precise medicine malignant tumors.

Language: Английский

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Dendrimer-Mediated Generation of a Metal-Phenolic Network for Antibody Delivery to Elicit Improved Tumor Chemo/Chemodynamic/Immune Therapy

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

To simplify the composition and improve efficacy of metal-phenolic network (MPN)-based nanomedicine, herein, we designed an MPN platform to deliver programmed death ligand-1 (PD-L1) antibody (anti-PD-L1) for combined tumor chemo/chemodynamic/immune therapy. Here, generation 5 poly(amidoamine) dendrimers conjugated with gossypol (Gos) through boronic ester bonds were used as a synthetic polyphenol coordinate Mn2+, then complexed anti-PD-L1 obtain nanocomplexes (for short, DPGMA). The prepared DPGMA exhibited good water dispersibility hydrodynamic size 166.3 nm tumor-microenvironment-responsive drug release behavior. integration Gos Mn2+ within resulted in significant inhibition immunogenic cell activation Gos-mediated chemotherapy Mn2+-catalyzed chemodynamic therapy, respectively, thereby leading dendritic maturation due role played mediate stimulator interferon genes (STING) pathway. Moreover, promoted recognition uptake by PD-L1-overexpressed tumors targeting, achieving combinational therapy mouse melanoma model, where immunotherapy modes three parts via chemotherapy/CDT-mediated ICD, Mn2+-mediated STING activation, antibody-mediated immune checkpoint blockade. With Mn2+-endowed r1 relaxivity (1.38 mM–1 s–1), can also be MR imaging. dendrimer-mediated may developed advanced nanomedicine tackle other cancer types.

Language: Английский

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