Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy DOI Creative Commons
Xiaoyan Qi, Cheng Cheng, Dawei Zhang

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Дек. 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

Язык: Английский

Epithelial-Mesenchymal Transition in Tumor Cells and Activated Intra-Tumor Immunity Respectively Are Correlated With Prognosis and Chemo-Sensitivity in Breast Cancer Patients With a Non-pathological Response to Neoadjuvant Chemotherapy DOI Open Access
Junichi Kurebayashi, Takayuki Iwamoto,

Yoshikazu Koike

и другие.

Опубликована: Окт. 4, 2023

To clarify whether changes in biological features of breast tumor cells and intra-tumor immunity after neoadjuvant chemotherapy (NAC) may correlate with pathological responses prognosis cancer patients treated NAC, we investigated various biomarkers using both pre- post-NAC samples. The study subjects were 24 primary patients, who NAC at the Department Breast Thyroid Surgery, Kawasaki Medical School Hospital between 2010 2011. All them had a non-pathological complete response (pCR) to their samples available for biomarker assays. Ki67 labeling index, apoptosis, factors related stem epithelial-mesenchymal transition, infiltrating lymphocytes (TILs), expression levels CD-8, CD-4, FoxP3, PD-L1, PD-1 studied paired Biological characteristics residual tumors such as nuclear grade (NG) vascular invasion (v) also investigated. median age was 53 years-old 14 stage III tumors, while 10 II tumors. A higher level CD8, CD4, or pre-NAC CD4 PD-L1 significantly correlated better NAC. Positivity ZEB1, vimentin, v NG 3 either worse disease-free survival (DFS) overall (OS) by univariate analyses. Multivariate analyses DFS OS revealed that positivity vimentin independent prognostic this study. These findings indicate activated immune microenvironments play significant roles up-regulation v-positivity be pivotal non-pCR cases

Язык: Английский

Процитировано

1

Therapeutic implications of the interplay between interferons and ER in breast cancer DOI
Nataša Todorović‐Raković, Jonathan R. Whitfield

Cytokine & Growth Factor Reviews, Год журнала: 2024, Номер 75, С. 119 - 125

Опубликована: Янв. 5, 2024

Язык: Английский

Процитировано

0

Molecular mechanisms involved in therapeutic effects of natural compounds against cisplatin-induced cardiotoxicity: a review DOI
Mahvash Hesari, Pantea Mohammadi, Mojtaba Moradi

и другие.

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Июнь 8, 2024

Язык: Английский

Процитировано

0

Salvia miltiorrhiza bge. f. alba ameliorates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease via the STING pathway DOI
Donghui Huang,

Fuyan Bai,

Tingting Hu

и другие.

American Journal of Translational Research, Год журнала: 2024, Номер 16(8), С. 3678 - 3689

Опубликована: Янв. 1, 2024

To elucidate the functional role and underlying mechanism of Salvia miltiorrhiza bge. f. alba (SMBFA) in patients with type 2 diabetes mellitus (T2DM) accompanied by non-alcoholic fatty liver disease (NAFLD).

Язык: Английский

Процитировано

0

Loss of STING impairs lactogenic differentiation DOI Creative Commons
Ramiah R. Vickers, Garhett L. Wyatt,

Lilia Sanchez

и другие.

Development, Год журнала: 2024, Номер 151(19)

Опубликована: Окт. 1, 2024

ABSTRACT Heightened energetic and nutrient demand during lactogenic differentiation of the mammary gland elicits upregulation various stress responses to support cellular homeostasis. Here, we identify stimulator interferon genes (STING) as an immune supporter functional development mouse epithelial cells (MECs). An in vitro model MEC revealed that STING is activated a cGAS-independent manner produce both type I interferons proinflammatory cytokines response accumulation mitochondrial reactive oxygen species. Induction activity was found be dependent on breast tumor suppressor gene single-minded 2 (SIM2). Using models lactation, discovered loss results early involution #3 glands, severely impairing lactational performance. Our data suggest required for successful bestows differential phenotype between glands traditionally explored inguinal 4|9 pair. These findings affirm unique pairs essential consider future investigations into normal cancer initiation.

Язык: Английский

Процитировано

0

An insight into the role of innate immune cells in breast tumor microenvironment DOI

Sandini Garg,

Garima Rai,

Sakshi Singh

и другие.

Breast Cancer, Год журнала: 2024, Номер unknown

Опубликована: Окт. 26, 2024

Язык: Английский

Процитировано

0

In Silico Discovery of Multi-Target Natural Ligands and Efficient siRNA Design for Overcoming Drug Resistance in Breast Cancer via Local Therapy DOI Open Access

Seyed Mohammad Javad Hashemi,

Ali Barzegar, Javad Akhtari

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 11, 2024

Abstract In this study, we designed an efficient siRNA for PKMYT1 gene knockdown, and evaluated the binding affinities of different natural ligands to crucial proteins involved in breast cancer. Designed showed strong affinity minimal off-target effects. Molecular docking studies identified new as antagonists with high aromatase, estrogen receptor alpha, HER2, PARP10, well agonists MT2 STING. The ligand SCHEMBL7562664 was introduced a golden due its among multiple targets lack cytotoxic mutagenic Natural small molecules research, their multi-target characteristics, provided solution overcome problem drug resistance cancer cells. Furthermore, proposed three dimensional scaffold design local therapy offers promising approach increase delivery efficacy these molecules, reduce systemic side effects, improve treatment outcomes. significant favorable pharmacokinetic properties were identified, which paves way further research targeted

Язык: Английский

Процитировано

0

Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy DOI Creative Commons
Xiaoyan Qi, Cheng Cheng, Dawei Zhang

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Дек. 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

Язык: Английский

Процитировано

0