Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects

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

Published: Oct. 2, 2024

The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. agonists have shown potential enhancing immune responses, particularly tumors resistant to traditional therapies. This scholarly review examines the diverse categories agonists, encompassing CDN analogues, non-CDN chemotypes, CDN-infused exosomes, engineered bacterial vectors, and hybrid structures small molecules-nucleic acids. We highlight their mechanisms, clinical trial progress, therapeutic outcomes. While these agents offer significant promise, challenges such as toxicity, tumor heterogeneity, delivery methods remain obstacles broader use. Ongoing research innovation are essential overcoming hurdles. could play transformative role treatment, patients with hard-to-treat malignancies, by harnessing body's system eliminate cells.

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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Small Molecule Inhibitors Targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for Cancer Immunotherapy (2020-2024)

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 283, P. 117141 - 117141

Published: Dec. 5, 2024

Language: Английский

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Small molecule innate immune modulators in cancer therapy

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

Published: Sept. 10, 2024

Immunotherapy has proved to be a breakthrough in cancer treatment. So far, bulk of the approved/late-stage immunotherapy are antibody-based. Although these antibody-based drugs have demonstrated great promise, majority them limited due their access extracellular targets, lack oral bioavailability, tumor microenvironment penetration, induction antibody dependent cytotoxicity etc. In recent times, there been an increased research focus on development small molecule immunomodulators since they potential overcome aforementioned limitations posed by antibodies. Furthermore, while most biologics based therapeutics that clinical use modulating adaptive immune system, very few clinically approved therapeutic modalities exist modulate innate system. The which is body's first line defense, ability turn cold tumors hot and synergize strongly with existing modulators. preclinical studies, modulators synergistic efficacy as combination current standard-of-care checkpoint this review, we highlight advances made immunotherapy.

Language: Английский

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Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy

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

Published: Dec. 6, 2024

Cancer immunotherapy has revolutionized the treatment of various malignancies, particularly with advent immune checkpoint inhibitors and CAR-T cell therapies [1][2][3]. These approaches have yielded impressive outcomes in a subset patients, yet many still fail to achieve durable responses [4]. One key reasons for this disparity is presence an immunosuppressive tumor microenvironment (TME), which plays crucial role limiting effectiveness immune-based [5,6]. The TME comprises complex network cellular molecular components, including tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor (MDSCs), all contribute evasion progression [7][8][9].The STING (stimulator interferon genes) pathway emerged as promising target cancer due its ability bridge innate adaptive [10,11]. Upon activation by cytosolic DNA, triggers production type I interferons other pro-inflammatory cytokines, leading dendritic (DCs) subsequent priming [12]. This process initiating robust anti-tumor response.However, despite potential agonists stimulate powerful responses, their efficacy clinical settings been limited, primarily nature TME, can dampen initiated [13]. TAMs, Tregs, MDSCs, together hostile environment that inhibits effective responses.TAMs often adopt M2-like phenotype within characterized anti-inflammatory tissue-remodeling activities promote growth suppress [14]. Recent studies shown lead shift TAM polarization from M2 M1, enhancing secretion cytokines such TNF-α IL-12, are immunity. Tregs play dual maintaining homeostasis but hinder immunity inhibiting cytotoxic functions. Targeting through may decrease suppressive effects, allowing more response against [15].MDSCs represent significant barrier successful produce reactive oxygen species (ROS) factors inhibit activation.Emerging evidence suggests reduce MDSC levels or impair function, thereby alleviating suppression activity [16,17]. extracellular matrix (ECM) physical characteristics hypoxia acidosis, also suppression. enhance remodeling ECM, facilitating better infiltration improving therapeutic [18].Given these challenges, there growing interest exploring synergistic combination strategies not only modulate overall [19,20]. For instance, targeting specific components suppression, create favorable STING-mediated [21,22]. demonstrated combining like bispecific antibodies leads enhanced improved regression. approach great promise overcoming resistance mechanisms associated current immunotherapies. By leveraging multiple modalities, researchers aim ultimately patient [23]. article will delve into immunotherapy, how modulation treatments. uniquely contributes field systematically evaluating combined TME-modulating therapies, overlooked literature. Moreover, it emphasizes critical need personalized consider distinct individual microenvironments, optimizing efficacy. Additionally, manuscript outlines future research directions elucidate interacts paving way innovative applications. Unlike previous focus on isolated interventions, provides comprehensive overview diverse TME-targeting significantly optimize improve outcomes.TME dynamic entity [24,25]. It consists cells, fibroblasts, endothelial ECM [26]. Among MDSCs players [7][8][9].TAMs [27]. secrete IL-10 TGF-β, proliferation natural killer (NK) fostering protects attack [28]. another component functioning maintain tolerance prevent autoimmunity. However, context cancer, effector secreting TGF-β. escape them proliferate unchecked [29]. heterogeneous population immature myeloid expand during chronic inflammatory conditions. Within function ROS, nitric oxide (NO), arginase, further contributing [30]. present challenges immunotherapy. creates barriers, dense impede agents tumor. hypoxic acidic conditions commonly found exacerbate therapy [31].In addition previously discussed non-cellular roles. Endothelial line blood vessels, essential supplying nutrients [32]. they overexpress adhesion molecules chemokines, attracting thus suppressing anti -tumor cells. Their abnormal vessel structure impairs drug delivery favors survival metastasis [33].Stroma especially creating fibrotic restricts [34,35]. They affecting cells' behavior, understanding crosstalk devising agonists.Tumor root problem, downregulate MHC expression, TGF -β IL -10, undergo alterations [36]. A interactions developing those integrating agonists, outcomes.Addressing requires restore be possible reprogram state one supports immunity, immunotherapy.The system, playing pivotal detecting originates viral infections damaged cells.Upon recognition cyclic GMP-AMP synthase (cGAS) enzyme produces (cGAMP), second messenger directly activates protein [37].Once activated, translocates endoplasmic reticulum Golgi apparatus, where signaling cascade phosphorylation factor 3 (IRF3) (IFNs) [38].Type IFNs, IFN-α IFN-β, bridging responses. activate DCs, antigen presentation, lymphocytes (CTLs), destroying [39]. makes attractive initiate capable TME. Preclinical induce potent tumors. convert "cold" tumors-those low infiltration-into "hot" tumors responsive In promoting infiltration, direct induction death certain types, control [40]. translation encountered challenges. activation, when used monotherapy [41]. Furthermore, systemic administration carries risk inducing excessive inflammation, toxicity [42]. To overcome increasing strategies, [43]. Such immune-stimulating effects while mitigating influences maximizing immunotherapy.TME determining success failure As highly milieu, recruited interventions. poses challenge rely exert effects. Therefore, [44,45].One primary modulating tumors, pro-tumoral [46]. Reprogramming TAMs M1 agonists. M1-like support macrophage burden making permissive induced [47].In approach. reducing number enhanced. Combining Treg depletion could stronger sustained [48].MDSCs ROS NO, among [49]. Reducing blocking alleviate major barriers When MDSC-targeting removing source [50].As we explored ways becomes evident aspects require attention. -angiogenic normalizes vasculature, agonist [51,52].Engineering using drugs -promoting surface, molecule expression transmigration, boost [53]. Regarding stroma multi -pronged viable. Inhibiting overproduction degradation, cytokine/growth -induced [54]. include upregulating secretion, genetic/epigenetic alterations. approaches, efficacy.Beyond Strategies normalize alter metabolic facilitate example, stiffness penetration both [55]. synergy between preclinical models, compared either alone. reprogramming immunologically active, likelihood eradication [10]. summarize please refer Table 1. conclusion, represents strategy resistant ones, offering new hope patients who do respond modalities.As area progresses, identify most combinations application maximize outcomes. Figure 1 illustrates elements microenvironment, pathway, described section. advancements [56]. proinflammatory immunity.However, monotherapies limited result, trials focused [57].One notable involves ADU-S100, results pembrolizumab, PD-1 inhibitor, advanced solid [58]. led increased higher rate, suggesting inhibitors, immune-modulating anti-CTLA-4antibodies [59,60]. DMXAA anti-CTLA-4 murine models resulted complete regression some cases, highlighting approaches.In mentioned novel agent MSA -2 candidate non -CDN bioactivity. investigations, remarkable potential. cervical -PD -1, efficacy.This [61]. involving -β/PD -L1 antibody, exhibited [62].These findings suggest valuable arsenal potentially avenues treating malignancies outcomes.In order enrich landscape several related emerged. TAK -676, developed Takeda, promise.In robustly increase production. This, turn, holds addresses converting ones treatment. Clinically, offers tool existing therapies. across different inflammation must carefully managed. Future should TMEs, targeted systems minimizing side effects.This integrated

Language: Английский

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