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

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