Background and Objective:Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung syndrome associated with high mortality and morbidity. Toll-like receptors (TLRs), key pattern-recognition receptors of innate immunity, mediate inflammatory responses to both infectious and sterile lung injury. Although TLR signaling has been increasingly implicated in ARDS pathogenesis, significant developmental and translational gaps remain, particularly in pediatric ARDS (PARDS). This review summarizes current evidence on TLR-mediated mechanisms in ARDS and PARDS, with emphasis on developmental regulation and translational relevance. Methods:A narrative review was conducted using English-language studies identified from PubMed/MEDLINE and Google Scholar databases. Experimental, translational, and clinical studies investigating TLR signaling in ARDS and PARDS were reviewed, including studies involving cell-surface and endosomal TLRs, developmental immunology, animal models, genetic and transcriptomic analyses, and therapeutic modulation of TLR pathways or their key effector cytokines. Key Content and Findings:TLR4 is an extensively studied receptor in ARDS, mediating inflammatory responses to endotoxins, sterile injury, sepsis, and ventilator-induced lung injury (VILI) through MyD88- and TRIF-dependent pathways. Endosomal TLRs, including TLR3, TLR7, and TLR9, contribute predominantly to viral-induced lung injury and antiviral immunity. Experimental studies demonstrate that TLR activation drives cytokine amplification, neutrophil recruitment, endothelial dysfunction, and alveolar-capillary barrier disruption. Human studies identify TLR-associated polymorphisms and transcriptomic alterations linked to ARDS susceptibility and outcomes. Importantly, pediatric immune responses exhibit developmental regulation of TLR signaling, with age-dependent variation in receptor expression and cytokine production, suggesting PARDS pathogenesis involving TLR activation cannot be directly inferred from adult disease models. However, direct TLR-focused studies in PARDS remain limited. Conclusions:TLR signaling pathways are central to ARDS and PARDS pathogenesis and represent potential therapeutic targets. However, direct evidence in PARDS remains limited. Future research should prioritize age-stratified pediatric studies to define developmental differences in TLR signaling and guide therapeutic development.
Melanoma has one of the highest propensities to metastasize to the brain, and despite major advances with immune checkpoint inhibitors, brain metastases remain a leading cause of morbidity and mortality. The biological mechanisms governing brain colonization, immune evasion, and resistance to therapy are incompletely understood. This review summarizes recent advances in the understanding of the tumor microenvironment and signaling pathways involved in melanoma brain metastasis, with emphasis on mechanisms that may provide novel therapeutic opportunities. We performed a review of preclinical and clinical studies investigating molecular pathways, immune-cell interactions, and metabolic programs associated with melanoma brain metastasis and response to immunotherapy. Emerging evidence identifies enhancer of zeste homolog 2 (EZH2) phosphorylation by Src kinase as a key driver of brain metastasis through granulocyte colony-stimulating factor (G-CSF) production and recruitment of immunosuppressive neutrophils. Microglia and tumor-associated macrophages constitute major components of the brain metastatic microenvironment and actively support tumor progression. Spleen tyrosine kinase (Syk) signaling contributes to microglial activation and immune-related neurotoxicity during anti-programmed death 1 (PD-1) therapy. Mitochondrial dysfunction, including alterations in mitochondrial contact site and cristae organizing system (MICOS) complex components such as Mic19 and Mic60, promotes innate immune signaling through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and TANK-binding kinase 1 (TBK1). TBK1 emerges as a central regulator linking neuroinflammation, microglial activation, metastatic progression, and therapeutic resistance. In addition, metabolic reprogramming mediated by tectonic family member 1 (TCTN1) and carnitine palmitoyltransferase 1A (CPT1A) enhances fatty acid oxidation and promotes melanoma metastasis. These pathways may represent actionable targets that complement immune checkpoint blockade. Melanoma brain metastasis is driven by complex interactions between tumor cells, neutrophils, microglia, and mitochondrial signaling networks. Src-EZH2, TBK1-dependent inflammatory pathways, and TCTN1/CPT1A-mediated metabolic reprogramming are emerging biomarkers and therapeutic targets. Integrating these approaches with anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies may improve disease control, overcome resistance, and reduce immune-related adverse events in patients with melanoma brain metastases.
Background:Renal cell carcinoma (RCC) patients with rheumatoid arthritis (RA) represent a niche but understudied population that often suffers from comorbid frailty. Frailty and RA may adversely affect treatment and mortality outcomes in patients with cancer. We aim to evaluate the association between RA and mortality/treatment outcomes in patients with RCC, with attention to the impact of frailty on these associations. Methods:Retrospective cohort study examining patients aged 65 and older, with Medicare part A and B coverage and non-metastatic clear cell renal cell carcinoma (ccRCC) diagnosed between 2004-2017 via the Surveillance Epidemiology and End Results (SEER)-Medicare database. Patients stratified by RA, defined by having 2 or more ICD-9 and ICD-10 codes 30 to 365 days apart, and frailty status with a score of ≥0.25 using a validated claims-based frailty index (Kim et al. 2018). Receipt of immunotherapy and cancer-related surgery were assessed and compared. Cox proportional hazards regression models evaluated the association between RA, frailty and mortality (all-cause and cancer-specific). Competing risk analysis using fine-gray model used to assess interaction between RA and frailty with mortality. Results:The population included 31,989 patients, of which 802 patients had RA and 3,918 were frail. Approximately 60% of the population was male. Rates of cancer-related surgery were not significantly changed by RA status. No significant difference in immunotherapy administration based on RA status was observed [odds ratio (OR) 0.81, 95% confidence interval (CI): 0.59-1.12]. Frailty modified the relationship between RA and all-cause mortality (P=0.01). RA was associated with higher all-cause mortality risk in non-frail patients [hazard ratio (HR) 1.15, 95% CI: 1.03-1.29], but no difference in risk in frail patients (HR 0.94, 95% CI: 0.79-1.14). Frailty was associated with a higher risk of cancer-specific mortality (HR 1.37, 95% CI: 1.26-1.50), while RA was not (HR 1.08, 95% CI: 0.91-1.29). Conclusions:RA was an independent risk factor for all-cause mortality in non-frail patients with non-metastatic ccRCC, but not in frail patients. Frailty interacts with RA on the risk of all-cause mortality in this population. The presence of frailty, but not RA, was an independent risk factor for cancer-specific mortality. RA did not appear to significantly impact the receipt of immunotherapy and cancer-related surgery. The complex contributions of frailty and RA to mortality underscore the need for interdisciplinary collaboration between rheumatologists and oncologists in order to maximize treatment and mortality outcomes.
