Background: Exosomes are emerging as important mediators of the cross-talk between tumor cells and the microenvironment. The communication between tumor-derived exosomes and macrophages has a critical role in facilitating tumor progression. However, the mechanisms by which exosomes modulate tumor development in lung cancer are not fully understood. Methods: Short hairpin RNA mediated knockdown or exogenous expression of TRIM59 combined with in vitro and in vivo assays were performed to prove the functional significance of TRIM59. Western blotting, real-time PCR, co-immunoprecipitation, immunofluorescence (IF) staining assays, proximity ligation assay (PLA), ubiquitination assays, lactate secretion and lipid droplets content measurement, and rescue experiments were used to evaluate the mechanism. Lewis lung carcinoma (LLC) cells were injected via subcutaneously or tail vein into C57BL/6 wild-type (WT) and transgenic mice to assess the role of TRIM59 in vivo. Results: We demonstrated that tripartite motif-containing 59 (TRIM59) was expressed in lung cancer cells-derived exosomes, and can be transferred to macrophages through the exosomes. Activated macrophages by TRIM59 promote lung cancer progression in vitro and in vivo. Mechanistic investigations revealed that TRIM59 physically interacts with abhydrolase domain containing 5 (ABHD5) and directly induced the ubiquitination of ABHD5 and led to its proteasome-dependent degradation. ABHD5, an lipolytic co-activator, deficiency induced metabolic reprogramming and enabled NLRP3 inflammasome activation in macrophages. Further studies showed that the exacerbation of NLRP3 inflammasome activation by ABHD5 deficiency, provides a positive feedback loop to promote cancer progression by preferentially secrete the proinflammatory cytokine IL-1β. Conclusions: Collectively, these data indicate that tumor-derived exosomal TRIM59 converts macrophages to tumor-promoting functions of macrophages via regulating ABHD5 proteasomal degradation, to activate NLRP3 inflammasome signaling pathway to promote lung cancer progression by IL-1β secretion. Our findings also indicate that tumor-derived exosomal TRIM59 has an important role in intercellular communication for fostering an inflammatory microenvironment and promoting lung metastasis.

Background: Alterations in several tripartite motif-containing (TRIM) family proteins have been implicated in the pathogenesis of lung cancer. TRIM28, a member of the TRIM E3 ligase family, has been associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression and its role in the immune microenvironment of non-small cell lung cancer (NSCLC).Methods: We assessed the clinical significance of TRIM28 in tissue microarrays and TCGA cohorts. We investigated the function of TRIM28 in syngeneic mouse tumor models, theKras^LSL−G12D/+;Tp53^fl/fl(KP) mouse model, and humanized mice. Immune cell composition was analyzed using flow cytometry and immunohistochemistry.Results: Our findings revealed a positive correlation between TRIM28 expression and the infiltration of suppressive myeloid-derived suppressor cells (MDSCs) in NSCLC. Moreover, silencing TRIM28 enhanced the efficacy of anti-PD-1 immunotherapy by reshaping the inflamed tumor microenvironment. Mechanistically, we demonstrated that TRIM28 could physically interact with receptor-interacting protein kinase 1 (RIPK1) and promote K63-linked ubiquitination of RIPK1, which is crucial for sustaining activation of the NF-κB pathway. Mutagenesis of the E3 ligase domain corroborated the essential role of E3 ligase activity in TRIM28-mediated NF-κB activation. Further experiments revealed that TRIM28 could upregulate the expression of CXCL1 by activating NF-κB signaling. CXCL1 could bind to CXCR2 on MDSCs and promote their migration to the tumor microenvironment. TRIM28 knockdown increased responsiveness to anti-PD-1 therapy in immunocompetent mice, characterized by increased CD8⁺T tumor-infiltrating lymphocytes and decreased MDSCs.Conclusion: The present study identified TRIM28 as a promoter of chemokine-driven recruitment of MDSCs through RIPK1-mediated NF-κB activation, leading to the suppression of infiltrating activated CD8⁺T cells and the development of anti-PD-1 resistance. Understanding the regulation of MDSC recruitment and function by TRIM28 provides crucial insights into the association between TRIM28 signaling and the development of an immunosuppressive tumor microenvironment. These insights may inform the development of combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in NSCLC.

Introduction Stenotrophomonas maltophilia is an opportunistic pathogen associated with various nosocomial infections and is known for its intrinsic multidrug resistance. This study aims to provide a comprehensive overview of the epidemiology and resistance patterns of S. maltophilia in China from 2014 to 2021. Methods Data were extracted from the China Antimicrobial Resistance Surveillance System (CARSS) and the Blood Bacterial Resistance Investigation Collaborative System (BRICS), encompassing 1412 medical institutions across 31 provinces in China. We analyzed the prevalence of S. maltophilia in clinical isolates, focusing on specific patient populations and departments, as well as resistance profiles to recommended first-line antibiotics, including sulfamethoxazole-trimethoprim, levofloxacin, and minocycline. Results A total of 514,768 S. maltophilia strains were analyzed. The overall prevalence of S. maltophilia among all clinical bacterial isolates remained stable at approximately 2.1%, with higher rates observed in intensive care units and elderly patients. Resistance rates to sulfamethoxazole-trimethoprim decreased from 9.8% in 2014 to 7.5% in 2021. In contrast, resistance to levofloxacin showed a slight upward trend, increasing from 8.5% in 2014 to 9.5% in 2021. Meanwhile, minocycline resistance remained low, fluctuating marginally from 2.7% in 2014 to 1.7% in 2021. Conclusions This study highlights the stable prevalence of S. maltophilia in clinical settings in China and the overall low resistance rates to recommended first-line antibiotics. However, alarmingly high resistance rates were observed in specific specimen types, particularly in blood cultures, suggesting that minocycline may be the only reliable therapeutic option among the six tested antibiotics for treating such infections in China. Continuous surveillance and effective infection control measures are essential to manage S. maltophilia infections, particularly in vulnerable populations. Future research should focus on measuring the true burden of these infections and monitoring the susceptibility of the newly introduced antibiotics, such as cefiderocol.

Background: Bloodstream infections caused by carbapenem-resistant Gram-negative bacteria represent a critical global health challenge. This study aims to quantify the global and regional burden of bloodstream infections associated with and attributable to carbapenem-resistant Gram-negative bacteria in 2019. Methods: We extracted data from the MICROBE database, which encompasses information on the estimated burden of 23 pathogens and 88 pathogen-drug combinations for 12 major infectious syndromes across 204 countries and territories in 2019. The number and rate of deaths, as well as disability-adjusted life-years linked to bloodstream infections, were systematically analyzed. Findings: In 2019, bloodstream infections accounted for approximately 2.91 (95% UI, 1.74-4.53) million deaths globally, with Gram-negative bacteria responsible for 51.1% of these fatalities. An estimated 391,800 (95% UI 221,500-631,400) deaths were associated with carbapenem resistance, constituting 26.3% of all bloodstream infection-related deaths. The highest burden of carbapenem resistance was seen in South Asia, East Asia, and Eastern Europe, while the lowest burden was in Sub-Saharan Africa. Notably, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the leading carbapenem-resistant pathogens contributing to mortality. Interpretation: Our findings underscore the significant global burden of bloodstream infections caused by carbapenem-resistant Gram-negative bacteria, with notable regional disparities. There is an urgent need for enhanced surveillance, improved infection prevention and control measures, and better access to first-line antibiotics, particularly in high-burden regions. Addressing the threat of carbapenem resistance in bloodstream infections is essential for reducing mortality and improving health outcomes worldwide. Funding: The study was supported by the Special Research Start-up Fund for Recruited Talent of the First Affiliated Hospital of Wannan Medical College (YR202408) and Anhui Philosophy and Social Science Planning Project (AHSKQ2020D130). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: This study utilized data from public, exempting it from Ethics Committee approval.

Purpose: This study aimed to assess and predict the global and regional burden of candidemia. Methods: We extracted data on the estimated burden of candidemia from 1990 to 2021 from the MICROBE database. The number of deaths, age-standardized mortality of rate(ASMR) and disability-adjusted life-years(DALYs) associated with candidemia, were systematically analyzed. The burden of candidemia over the next 30 years was predicted using the Bayesian age-period-cohort model with integrated nested Laplace approximations. Results: In 2021, candidemia accounted for approximately 174,716 deaths(95% UI, 159,876–189,556) globally, with an ASMR of 2.28 (95% UI, 2.06–2.50) per 100k population. The highest burden of candidemia was observed in Southern, Western, and Eastern Sub-Saharan Africa, while the lowest burden occurred in High-income Asia Pacific, Australasia, and Western Europe. Males and older adults exhibited a higher disease burden, while the under-5 age group also demonstrated a substantial burden. Projections indicated that the mortality rate of candidemia was expected to decline to 1.72 per 100k(95% UI: 1.45–2.00) by 2050. Conclusions: Our findings underscore the significant global burden of candidemia, with notable regional disparities. Addressing this burden requires enhanced surveillance, robust antifungal stewardship programs, targeted interventions for high-risk populations, and improved diagnostic and therapeutic capabilities to mitigate the impact of antifungal resistance and reduce mortality.