m6A-dependent mature miR-151-5p accelerates the malignant process of HNSCC by targeting LYPD3.

miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3'-untranslated regions (3'-UTR) in the mRNA of LYPD3. Consequently, this interaction accelerates the metastasis of HNSCC. Notably, clinical observations indicate a correlation between high expression of miR-151-5p and low levels of LYPD3 in clinical settings are correlated with poor prognosis of HNSCC patients. Furthermore, our investigation demonstrates that glycosylation of LYPD3 modulates its subcellular localization and reinforces its role in suppressing HNSCC metastasis. Additionally, we uncover a potential regulatory mechanism involving the facilitation of miR-151-5p maturation and accumulation through N6-methyladenosine (m6A) modification. This process is orchestrated by methyltransferase-like 3 (METTL3) and mediated by a newly identified reader, heterogeneous nuclear ribonucleoprotein U (hnRNP U). These findings collectively underscore the significance of the METTL3/miR-151-5p/LYPD3 axis serves as a prominent driver in the malignant progression of HNSCC.

PA28γ coordinates the cross-talk between cancer-associated fibroblasts and tumor cells to promote OSCC progression via HDAC1/E2F3/IGF2 signaling.

PA28γ overexpression is aberrant and accompanied by poor patient prognosis in various cancers, the precise regulatory mechanism of this crucial gene in the tumor microenvironment remains incompletely understood. In this study, using oral squamous cell carcinoma as a model, we demonstrated that PA28γ exhibits high expression in cancer-associated fibroblasts (CAFs), and its expression significantly correlates with the severity of clinical indicators of malignancy. Remarkably, we found that elevated levels of secreted IGF2 from PA28γ+ CAFs can enhance stemness maintenance and promote tumor cell aggressiveness through the activation of the MAPK/AKT pathway in a paracrine manner. Mechanistically, PA28γ upregulates IGF2 expression by stabilizing the E2F3 protein, a transcription factor of IGF2. Further mechanistic insights reveal that HDAC1 predominantly mediates the deacetylation and subsequent ubiquitination and degradation of E2F3. Notably, PA28γ interacts with HDAC1 and accelerates its degradation via a 20S proteasome-dependent pathway. Additionally, PA28γ+ CAFs exert an impact on the tumor immune microenvironment by secreting IGF2. Excitingly, our study suggests that targeting PA28γ+ CAFs or secreted IGF2 could increase the efficacy of PD-L1 therapy. Thus, our findings reveal the pivotal role of PA28γ in cell interactions in the tumor microenvironment and propose novel strategies for augmenting the effectiveness of immune checkpoint blockade in oral squamous cell carcinoma.

PA28γ induces dendritic cell maturation and activates T-cell immune responses in oral lichen planus.

Oral lichen planus (OLP) is a common chronic inflammatory disease of the oral mucosa, the mechanism of its inflammatory progression has not yet been fully elucidated. PA28γ plays a significant role in a variety of immune-related diseases. However, the exact role of PA28γ in the pathogenesis of OLP remains unclear. Here, we demonstrated that PA28γ is overexpressed in epithelial cells and inflammatory cells of OLP tissues but has no significant relationship with OLP subtypes. Functionally, keratinocytes with high PA28γ expression could induce dendritic cell (DC) maturation and promote the T-cell differentiation into Th1 cells in response to the immune response. In addition, we found that a high level of PA28γ expression is associated with high numbers of infiltrating mature DCs and activated T-cells in OLP tissues. Mechanistically, keratinocytes with high PA28γ expression could promote the secretion of C-C motif chemokine (CCL)5, blocking CCL5 or/and its receptor CD44 could inhibit the induction of T-cell differentiation by keratinocytes with high PA28γ expression. In conclusion, we reveal that keratinocytes with high expression of PA28γ in OLP can induce DC maturation and promote T-cell differentiation through the CCL5-CD44 pathway, providing previously unidentified mechanistic insights into the mechanism of inflammatory progression in OLP.

A chimeric adenovirus-vectored vaccine based on Beta spike and Delta RBD confers a broad-spectrum neutralization against Omicron-included SARS-CoV-2 variants.

Urgent research into innovative severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus-vectored vaccine named Ad5-Beta/Delta. This vaccine was created by incorporating the receptor-binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5-Beta/Deta vaccine induced robust broad-spectrum neutralization against Omicron BA.5-included variants. IN immunization with Ad5-Beta/Delta vaccine exhibited superior mucosal immunity, manifested by higher secretory IgA antibodies and more tissue-resident memory T cells (TRM) in respiratory tract. The combination of IM and IN delivery of the Ad5-Beta/Delta vaccine was capable of synergically eliciting stronger systemic and mucosal immune responses. Furthermore, the Ad5-Beta/Delta vaccination demonstrated more effective boosting implications after two dosages of mRNA or subunit recombinant protein vaccine, indicating its capacity for utilization as a booster shot in the heterologous vaccination. These outcomes quantified Ad5-Beta/Delta vaccine as a favorable vaccine can provide protective immunity versus SARS-CoV-2 pre-Omicron variants of concern and BA.5-included Omicron subvariants.

Lung microbiome: new insights into the pathogenesis of respiratory diseases.

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community. The microbiome of healthy lungs is mainly derived from the upper respiratory tract (URT) microbiome but also has its own characteristic flora. The selection mechanisms in the lung, including clearance by coughing, pulmonary macrophages, the oscillation of respiratory cilia, and bacterial inhibition by alveolar surfactant, keep the microbiome transient and mobile, which is different from the microbiome in other organs. The pulmonary bacteriome has been intensively studied recently, but relatively little research has focused on the mycobiome and virome. This up-to-date review retrospectively summarizes the lung microbiome's history, composition, and function. We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses. More importantly, we focus on multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), fibrosis, bronchiectasis, and pneumonia. The impact of the lung microbiome on coronavirus disease 2019 (COVID-19) and lung cancer has also been comprehensively studied. Furthermore, by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field, we propose an outlook of the direction of lung microbiome research.

Biofilm formation: mechanistic insights and therapeutic targets.

Biofilms are complex multicellular communities formed by bacteria, and their extracellular polymeric substances are observed as surface-attached or non-surface-attached aggregates. Many types of bacterial species found in living hosts or environments can form biofilms. These include pathogenic bacteria such as Pseudomonas, which can act as persistent infectious hosts and are responsible for a wide range of chronic diseases as well as the emergence of antibiotic resistance, thereby making them difficult to eliminate. Pseudomonas aeruginosa has emerged as a model organism for studying biofilm formation. In addition, other Pseudomonas utilize biofilm formation in plant colonization and environmental persistence. Biofilms are effective in aiding bacterial colonization, enhancing bacterial resistance to antimicrobial substances and host immune responses, and facilitating cell‒cell signalling exchanges between community bacteria. The lack of antibiotics targeting biofilms in the drug discovery process indicates the need to design new biofilm inhibitors as antimicrobial drugs using various strategies and targeting different stages of biofilm formation. Growing strategies that have been developed to combat biofilm formation include targeting bacterial enzymes, as well as those involved in the quorum sensing and adhesion pathways. In this review, with Pseudomonas as the primary subject of study, we review and discuss the mechanisms of bacterial biofilm formation and current therapeutic approaches, emphasizing the clinical issues associated with biofilm infections and focusing on current and emerging antibiotic biofilm strategies.

Evolution of lasR mutants in polymorphic Pseudomonas aeruginosa populations facilitates chronic infection of the lung.

Chronic infection with the bacterial pathogen Pseudomonas aeruginosa often leads to coexistence of heterogeneous populations carrying diverse mutations. In particular, loss-of-function mutations affecting the quorum-sensing regulator LasR are often found in bacteria isolated from patients with lung chronic infection and cystic fibrosis. Here, we study the evolutionary dynamics of polymorphic P. aeruginosa populations using isolates longitudinally collected from patients with chronic obstructive pulmonary disease (COPD). We find that isolates deficient in production of different sharable extracellular products are sequentially selected in COPD airways, and lasR mutants appear to be selected first due to their quorum-sensing defects. Polymorphic populations including lasR mutants display survival advantages in animal models of infection and modulate immune responses. Our study sheds light on the multistage evolution of P. aeruginosa populations during their adaptation to host lungs.

An integrated multi-omics analysis of identifies distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.

Chronic pulmonary bacterial infection facilitates breast cancer lung metastasis by recruiting tumor-promoting MHCIIhi neutrophils.

Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCIIhi neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCIIhi neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCIIhi neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCIIhi neutrophils as the principal mediator between chronic infection and tumor metastasis.

circFANCA accelerates the malignant process of OSCC by modulating miR-34a/PA28γ signaling.

OBJECTIVES: To investigate the upstream regulatory molecules of proteasomal activator 28γ (PA28γ), and explore its specific regulatory mechanism and potential clinical significance in OSCC. MATERIALS AND METHODS: qPCR was used to examine miR-34a, circFANCA and PSME3 expression. Western blotting was adopted to detect PA28γ expression. Transwell experiments were conducted to evaluate OSCC cell migration and invasion ability. FISH was used to evaluate the subcellular localization of circFANCA and miR-34a, and RNA pull-down verified the interaction between them. The expression of circFANCA and miR-34a in clinical cohorts was assessed by ISH, and the results were subjected to survival analysis using Kaplan-Meier analysis. RESULTS: Here, we proved that miR-34a expression is lower in highly aggressive OSCC tissues and cell lines. Notably, miR-34a can downregulate PA28γ expression and inhibit OSCC invasion and migration. Next, we confirmed that circFANCA promoted OSCC cell metastatic ability by sponging miR-34a. Importantly, interfering with miR-34a rescued the malignant progression of OSCC induced by silencing circFANCA. Finally, clinical data showed lower miR-34a expression and higher circFANCA expression were associated with poor prognosis in OSCC patients. CONCLUSION: The circFANCA/miR-34a/PA28γ axis facilitates the metastasis of OSCC, and circFANCA and miR-34a have potential to serve as prognostic markers for OSCC patients.

Intricate confrontation: Research progress and application potential of TRIM family proteins in tumor immune escape.

BACKGROUND: Tripartite motif (TRIM) family proteins have more than 80 members and are widely found in various eukaryotic cells. Most TRIM family proteins participate in the ubiquitin-proteasome degradation system as E3-ubiquitin ligases; therefore, they play pivotal regulatory roles in the occurrence and development of tumors, including tumor immune escape. Due to the diversity of functional domains of TRIM family proteins, they can extensively participate in multiple signaling pathways of tumor immune escape through different substrates. In current research and clinical contexts, immune escape has become an urgent problem. The extensive participation of TRIM family proteins in curing tumors or preventing postoperative recurrence and metastasis makes them promising targets. AIM OF REVIEW: The aim of the review is to make up for the gap in the current research on TRIM family proteins and tumor immune escape and propose future development directions according to the current progress and problems. KEY SCIENTIFIC CONCEPTS OF REVIEW: This up-to-date review summarizes the characteristics and biological functions of TRIM family proteins, discusses the mechanisms of TRIM family proteins involved in tumor immune escape, and highlights the specific mechanism from the level of structure-function-molecule-pathway-phenotype, including mechanisms at the level of protein domains and functions, at the level of molecules and signaling pathways, and at the level of cells and microenvironments. We also discuss the application potential of TRIM family proteins in tumor immunotherapy, such as possible treatment strategies for combination targeting TRIM family protein drugs and checkpoint inhibitors for improving cancer treatment.

Single-cell transcriptomics reveals distinct cell response between acute and chronic pulmonary infection of Pseudomonas aeruginosa.

Knowledge of the changes in the immune microenvironment during pulmonary bacterial acute and chronic infections is limited. The dissection of immune system may provide a basis for effective therapeutic strategies against bacterial infection. Here, we describe a single immune cell atlas of mouse lungs after acute and chronic Pseudomonas aeruginosa infection using single-cell transcriptomics, multiplex immunohistochemistry, and flow cytometry. Our single-cell transcriptomic analysis revealed large-scale comprehensive changes in immune cell composition and high variation in cell-cell interactions after acute and chronic P. aeruginosa infection. Bacterial infection reprograms the genetic architecture of immune cell populations. We identified specific immune cell types, including Cxcl2+ B cells and interstitial macrophages, in response to acute and chronic infection, such as their proportions, distribution, and functional status. Importantly, the patterns of immune cell response are drastically different between acute and chronic infection models. The distinct molecular signatures highlight the importance of the highly dynamic cell-cell interaction process in different pathological conditions, which has not been completely revealed previously. These findings provide a comprehensive and unbiased immune cellular landscape for respiratory pathogenesis in mice, enabling further understanding of immunologic mechanisms in infection and inflammatory diseases.

Repurposing Dimetridazole and Ribavirin to disarm Pseudomonas aeruginosa virulence by targeting the quorum sensing system.

Pseudomonas aeruginosa relies on its complex cellular regulatory network to produce a series of virulence factors and to cause various acute and chronic infections in a wide range of hosts. Compared with traditional antibiotics which frequently accompany with widespread antibiotic resistance, crippling the virulence system of bacteria is expected to be a promising anti-infective strategy. In this study, Dimetridazole and Ribavirin, which had poor antibacterial activities on P. aeruginosa reference isolate PAO1 in nutrient medium but significantly inhibited the growth of P. aeruginosa PAO1 in M9-adenosine, were selected from 40 marketed compounds with similar core structure (furan, benzofuran, or flavonoids) to the acyl-homoserine lactone signals of P. aeruginosa quorum sensing (QS) system. The production of QS-controlled proteases, pyocyanin, and biofilm formation of P. aeruginosa PAO1 and the clinical isolates were significantly decreased by the presence of Dimetridazole or Ribavirin. Correspondingly, the majority of QS-activated genes in P. aeruginosa, including the key regulatory genes lasR, rhlR, and pqsR and their downstream genes, were significantly inhibited by Ribavirin or Dimetridazole, as determined by RNA-sequencing and quantitative PCR. Furthermore, the susceptibilities of drug-resistant P. aeruginosa isolates to polymyxin B, meropenem, and kanamycin were remarkably promoted by the synergistic application of Dimetridazole or Ribavirin. Finally, the treatment of Ribavirin or Dimetridazole effectively protected Caenorhabditis elegans and mice from P. aeruginosa infection. In conclusion, this study reports the antivirulence potentials of Dimetridazole and Ribavirin on P. aeruginosa and provides structural basis and methodological reference for the development of anti-pseudomonal drugs.

Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4-17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.

Extrachromosomal circular DNA (eccDNA): an emerging star in cancer.

Extrachromosomal circular DNA (eccDNA) is defined as a type of circular DNA that exists widely in nature and is independent of chromosomes. EccDNA has attracted the attention of researchers due to its broad, random distribution, complex biogenesis and tumor-relevant functions. EccDNA can carry complete gene information, especially the oncogenic driver genes that are often carried in tumors, with increased copy number and high transcriptional activity. The high overexpression of oncogenes by eccDNA leads to malignant growth of tumors. Regardless, the exact generation and functional mechanisms of eccDNA in disease progression are not yet clear. There is, however, an emerging body of evidence characterizing that eccDNA can be generated from multiple pathways, including DNA damage repair pathways, breakage-fusion-bridge (BFB) mechanisms, chromothripsis and cell apoptosis, and participates in the regulation of tumor progression with multiplex functions. This up-to-date review summarizes and discusses the origins, biogenesis and functions of eccDNA, including its contribution to the formation of oncogene instability and mutations, the heterogeneity and cellular senescence of tumor cells, and the proinflammatory response of tumors. We highlight the possible cancer-related applications of eccDNA, such as its potential use in the diagnosis, targeted therapy and prognostic assessment of cancer.

Impact of single-cell RNA sequencing on understanding immune regulation.

Single-cell RNA sequencing (scRNA-seq), one of the most powerful technologies, can describe the transcriptomic heterogeneity of single cells and reveal previously unreported cell types or states in complex tissues. With the rapid development of scRNA-seq, it has renewed our view of cellular heterogeneity and its significance for deeply understanding cell development and function. There are a large number of studies applying scRNA-seq to investigate the heterogeneity of immune cells and disease pathogenesis, focusing on differences among every individual cell, which have provided novel inspiration for disease therapy and biological processes. In this review, we describe the development of scRNA-seq and its application in immune-related physiological states, regulatory mechanisms and diseases. In addition, we further discuss the opportunities and challenges of scRNA-seq in immune regulation.

Extracellular Vesicles: Recent Insights Into the Interaction Between Host and Pathogenic Bacteria.

Extracellular vesicles (EVs) are nanosized lipid particles released by virtually every living cell. EVs carry bioactive molecules, shuttle from cells to cells and transduce signals, regulating cell growth and metabolism. Pathogenic bacteria can cause serious infections via a wide range of strategies, and host immune systems also develop extremely complex adaptations to counteract bacterial infections. As notable carriers, EVs take part in the interaction between the host and bacteria in several approaches. For host cells, several strategies have been developed to resist bacteria via EVs, including expelling damaged membranes and bacteria, neutralizing toxins, triggering innate immune responses and provoking adaptive immune responses in nearly the whole body. For bacteria, EVs function as vehicles to deliver toxins and contribute to immune escape. Due to their crucial functions, EVs have great application potential in vaccines, diagnosis and treatments. In the present review, we highlight the most recent advances, application potential and remaining challenges in understanding EVs in the interaction between the host and bacteria.

CircRFWD3 promotes HNSCC metastasis by modulating miR-27a/b/PPARγ signaling.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, the 5-year survival rate of patients with HNSCC is still about 50% due to frequent metastasis and recurrence. Circular RNAs (circRNAs) have been characterized as key regulators of gene expression in numerous malignancies. However, the role of circRNA in HNSCC metastasis remains largely unknown. Here, we demonstrated that the circRFWD3 was significantly upregulated in HNSCC tissues and cell lines by circRNA microarray analysis and qPCR. Notably, high expression of circRFWD3 is related to highly aggressive HNSCC cell lines and lymph node metastasis in HNSCC patients. After that, Sanger sequencing, RNase R, and actinomycin D assay were performed to verify the ring structure of circRFWD3. Then functional experiments found it could promote the metastasis of HNSCC cells both in vitro and in vivo. Mechanistically, a dual-luciferase reporter assay, FISH, RIP, RNA pull-down, RNA-seq, and western blot experiments were employed and found that circRFWD3 served as a miRNAs sponge for miR-27a/27b, leading to the upregulation of PPARγ, and then promoted HNSCC metastasis via NF-κB/MMP13 pathway. Finally, ISH and IHC were carried out to determine the expression levels and clinical significances of circRFWD3 and PPARγ in clinical cohorts of HNSCC. According to the analysis results from two independent HNSCC cohorts, upregulated expression of circRFWD3 and PPARγ were positively associated with worse survival in patients with HNSCC. Overall, our results uncover that circRFWD3 acts a critical role in promoting the aggressiveness of HNSCC cells and is a prognostic marker for the disease, indicating that circRFWD3 may act as a potential therapeutic target in HNSCC.

Subinhibitory Cefotaxime and Levofloxacin Concentrations Contribute to Selection of Pseudomonas aeruginosa in Coculture with Staphylococcus aureus.

Bacterial species in the polymicrobial community evolve interspecific interaction relationships to adapt to the survival stresses imposed by neighbors or environmental cues. Pseudomonas aeruginosa and Staphylococcus aureus are two common bacterial pathogens frequently coisolated from patients with burns and respiratory disease. Whether the application of commonly used antibiotics influences the interaction dynamics of the two species still remains largely unexplored. By performing a series of on-plate competition assays and RNA sequencing-based transcriptional profiling, we showed that the presence of the cephalosporin antibiotic cefotaxime or the quinolone antibiotic levofloxacin at subinhibitory concentration contributes to selecting P. aeruginosa from the coculture with S. aureus by modulating the quorum-sensing (QS) system of P. aeruginosa. Specifically, a subinhibitory concentration of cefotaxime promotes the growth suppression of S. aureus by P. aeruginosa in coculture. This process may be related to the increased production of the antistaphylococcal molecule pyocyanin and the expression of lasR, which is the central regulatory gene of the P. aeruginosa QS hierarchy. On the other hand, subinhibitory concentrations of levofloxacin decrease the competitive advantage of P. aeruginosa over S. aureus by inhibiting the growth and the las QS system of P. aeruginosa. However, pqs signaling of P. aeruginosa can be activated instead to overcome S. aureus. Therefore, this study contributes to understanding the interaction dynamics of P. aeruginosa and S. aureus during antibiotic treatment and provides an important basis for studying the pathogenesis of polymicrobial infections. IMPORTANCE Increasing evidence has demonstrated the polymicrobial characteristics of most chronic infections, and the frequent communications among bacterial pathogens result in many difficulties for clinical therapy. Exploring bacterial interspecific interaction during antibiotic treatment is an emerging endeavor that may facilitate the understanding of polymicrobial infections and the optimization of clinical therapies. Here, we investigated the interaction of cocultured P. aeruginosa and S. aureus with the intervention of commonly used antibiotics in clinic. We found that the application of subinhibitory concentrations of cefotaxime and levofloxacin can select P. aeruginosa in coculture with S. aureus by modulating P. aeruginosa QS regulation to enhance the production of antistaphylococcal metabolites in different ways. This study emphasizes the role of the QS system in the interaction of P. aeruginosa with other bacterial species and provides an explanation for the persistence and enrichment of P. aeruginosa in patients after antibiotic treatment and a reference for further clinical therapy.