Novel Strategies in Breast Cancer Management: from Treatment to Long-term Remission

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: unknown, P. 104715 - 104715

Published: April 1, 2025

Language: Английский

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Combining immune checkpoints with TNFSF agonists: a new horizon for cancer and autoimmune therapies

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 17, 2025

The immune response is orchestrated by a complex network of cytokines, which play fundamental role in both autoimmune diseases and cancer therapy. Immune checkpoint inhibitors (ICIs), target key inhibitory pathways such as PD-1/PD-L1 CTLA-4, have revolutionized immunotherapy reinstating T-cell activity overcoming evasion mechanisms [1]. Despite their success cancers like melanoma lung cancer, substantial number patients fail to respond ICIs. This resistance often due the lack pre-existing immunity, emergence mechanisms, or an immunosuppressive tumor microenvironment (TME), highlighting need for more targeted therapeutic strategies [2]. In this context, cytokines receptor networks, particularly those within necrosis factor superfamily (TNFSF) its receptors (TNFRSF), emerged pivotal players regulating responses.Figure 1 illustrates TNFSF signaling pathway. It shows structure unbound state interaction with receptor. Upon binding, forms receptor-ligand complex, depicted middle portion. lower part highlights downstream events following clustering. clustering activates TRAF2 plays critical modulating responses. These interactions are regulation enhance potential targeting [3]. Cytokines OX40, 4-1BB, CD40 promote activation, survival, proliferation, contributing anti-tumor immunity homeostasis However, constrained exhaustion effects TME, can limit efficacy, similarly ICIs [4]. (left), followed binding (green, blue, pink) (middle). right panel (orange) bound receptor, initiating formation complex. how ligandreceptor triggers leading essential responses.To overcome these limitations, combining agonists presents synergistic strategy. While unmask suppression restore responses, agonists, OX40 activation providing robust [5]. Furthermore, TNFR2 could modulate regulation, influencing regulatory activity, offering benefits 带格式的: 缩进: 首行缩进: 0 字符 diseases.However, integration also faces challenges, immunerelated adverse (irAEs), optimal dosing strategies, identifying who would benefit most from therapies. [6]. Precision medicine, guided biomarkers advanced diagnostic techniques, will be hurdles. Opinion Article explores offer novel approach cytokine networks advancing treatment outcomes cancer.ICIs therapy PD-1, PD-L1, restoring enhancing elimination. low infiltration emphasizing complementary [7].TNFSF CD40, provide complement amplifying proliferation through co-stimulatory signals [8]. CD4+ CD8+ while 4-1BB cytotoxicity natural killer (NK) cell activity. Similarly, stimulate antigen-presenting cells (APCs), fostering adaptive immunity. reduce counteract influences T (Tregs) myeloid-derived suppressor (MDSCs) TME. Table summarizes clinical development, including Urelumab Selicrelumab ABBV-927 diseases. agents highlight diverse applications combination potent immunotherapies raises concerns about immune-related release syndrome autoimmunity.Careful patient selection, biomarker-driven stratification, optimized mitigate risks.The synergy between arises mechanisms. it promotes tumor-free survival. some trials, therapies ipilimumab (a CTLA-4 inhibitor) BMS-986178 did not improve rate compared monotherapy. safety profiles combinations varied, common side lymphopenia, rash, pyrexia, fatigue.Further research needed optimize better [21].Clinical trials started explore various cancers, melanoma, non-small colorectal cancer. Early-phase PD-1 shown promising results, improved objective rates progressionfree survival [22][23][24]. blockade CD8 + T-cell-dependent manner murine gliomas. reduces TIL improves functionality. Efficacy correlates expression on TILs, location histology, license models where levels were previously [25]. being investigated ICIs, preliminary data suggesting enhanced regression durable responses [26][27][28]. when paired demonstrated ability convert immunologically cold tumors into hot ones, rendering them susceptible attack [29,30]. ongoing Phase I/II study, intratumoral sotigalimab (CD40 agonist) systemic pembrolizumab (anti-PD-1) was evaluated treatment-naïve, unresectable stage III/IV metastatic patients. As December 2021, 30 participants enrolled, well-tolerated no treatment-related discontinuations deaths. injection-site reactions, 6 experiencing grade-3 events. overall (ORR) 50% (5 complete 10 partial responses), disease control 67%. Notably, observed PD-L1 negative elevated LDH. Immunologic analyses showed increased higher clonality gene related antigen presentation, correlating efficacy warranting further investigation [31].Despite encouraging progress, significant challenges remain realizing full ICI agonist combinations. One primary risk irAEs. Both independently induce activation-related toxicities, (CRS), autoimmunity, inflammation. When combined, may exacerbate effects, necessitating careful dose optimization monitoring [32].Another challenge lies specificity. expressed multiple types, Tregs activated cells, off-target effects. For instance, Treg function settings, TME context-dependent, potentially favoring either activation. inadvertently activate pathogenic subsets, complicating outcomes. Patient stratification biomarker identification pose heterogeneity across different populations requires precision medicine identify likely Biomarkers expression, infiltration, guide but predictive value needs validation [33].Finally, logistical trial design execution must addressed [34]. CombiningICIs consideration schedules, administration sequences, partners maximize minimizing toxicity. Developing standardized protocols establishing endpoints accelerating translation practice.The offers opportunities diseases, addressing delicate balance suppression.ICIs, inhibitors, contexts, broad leads exacerbating autoimmunity [35,36]. contrast, approach, leveraging properties fine-tune [37].For example, candidates promoting expansion, maintaining tolerance mitigating hyperactive [38]. mechanism relevant rheumatoid arthritis, inflammation driven effector myeloid predominant. Studies that only enhances inflammatory macrophages dendritic cells. Additionally, DR3agonists selectively subsets without overactivating entire system. specificity especially valuable chronic conditions lupus sclerosis, system persistently hyperactive. By homeostasis, flares global immunosuppression [38,39]. erythematosus (SLE), Anifrolumab has positive results II III trials. August drug approved FDA moderate severe active SLE.Clinical improving organspecific markers, interferon-I [40,41].The create unique synergies.ICIs reactivate suppressed functionality reverse underlying viral infections, tolerogenic capacity existing treatments biologics small-molecule opens new avenues Targeted use achieve remission traditionally refractory single-agent therapies, representing advancement field therapeutics [42].The represents rapidly evolving area vast unmet fully realize potential, several areas demand focused innovation.While first-generation promise, types poses Next-generation should focus achieving controllable [43]. recent study development bispecific OX40-PD-L1 antibody, targets [9,44,45]. Advances antibody engineering, antibodies conditional allow precise delivery specific (TME) sites pathology. designing presence high other markers characteristic associated toxicities.One combinatory agonists. Biomarker paramount [46]. A Zhang et al. (2022) highlighted predict [35]. (e.g., cells), TNFRSF density selection high-throughput sequencing, single-cell analysis, artificial intelligence our prognostic biomarkers, paving way truly personalized immunotherapy.While benefits, amplified combined modalities [47]. Such Traditional Therapies:Combining chemotherapy radiotherapy Combining creating immunogenic [48].While current predominantly therapy, [36].Robust preclinical accurately recapitulate human predicting toxicity [49]. organoid systems, humanized mouse models, computational simulations findings success. Recent regimens, significantly [19]. On front, designs incorporating real-time accelerate effective therapies.The complexity necessitates collaboration disciplines [50]. Immunologists, oncologists, biologists, pharmaceutical scientists work together integrate insights basic research, practice, technological innovation. Partnerships academia, industry, agencies crucial streamlining pathway discovery implementation. Successful examples cross-disciplinary include progressed stages [22].The provides lifting suppression, allowing reactivation amplify effectively transforming "cold" "hot" ones bolstering diseases.Despite immense remain, regard irAEs, specificity, optimizing selection. diagnostics, nextgeneration safety. integrating interdisciplinary collaboration, strategy holds promise hope

Language: Английский

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CD40 promotes AML survival via non-canonical NF-κB signaling and aberrant lipid metabolism

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 156, P. 114665 - 114665

Published: April 18, 2025

Language: Английский

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The Ligands of the Tumor Necrosis Factor Superfamily and Their Receptors

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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