Targeted therapy for non-small-cell lung cancer: New insights into regulated cell death combined with immunotherapy.

Non-small-cell lung cancer (NSCLC), which has a high rate of metastatic spread and drug resistance, is the most common subtype of lung cancer. Therefore, NSCLC patients have a very poor prognosis and a very low chance of survival. Human cancers are closely linked to regulated cell death (RCD), such as apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Currently, small-molecule compounds targeting various types of RCD have shown potential as anticancer treatments. Moreover, RCD appears to be a specific part of the antitumor immune response; hence, the combination of RCD and immunotherapy might increase the inhibitory effect of therapy on tumor growth. In this review, we summarize small-molecule compounds used for the treatment of NSCLC by focusing on RCD and pharmacological systems. In addition, we describe the current research status of an immunotherapy combined with an RCD-based regimen for NSCLC, providing new ideas for targeting RCD pathways in combination with immunotherapy for patients with NSCLC in the future.

Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity.

Neurobiological consequences of traumatic brain injury (TBI) result from a complex interplay of secondary injury responses and sequela that mediates chronic disability. Endothelial cells are important regulators of the cerebrovascular response to TBI. Our work demonstrates that genetic deletion of endothelial cell (EC)-specific EPH receptor A4 (EphA4) using conditional EphA4f/f/Tie2-Cre and EphA4f/f/VE-Cadherin-CreERT2 knockout (KO) mice promotes blood-brain barrier (BBB) integrity and tissue protection, which correlates with improved motor function and cerebral blood flow recovery following controlled cortical impact (CCI) injury. scRNAseq of capillary-derived KO ECs showed increased differential gene expression of BBB-related junctional and actin cytoskeletal regulators, namely, A-kinase anchor protein 12, Akap12, whose presence at Tie2 clustering domains is enhanced in KO microvessels. Transcript and protein analysis of CCI-injured whole cortical tissue or cortical-derived ECs suggests that EphA4 limits the expression of Cldn5, Akt, and Akap12 and promotes Ang2. Blocking Tie2 using sTie2-Fc attenuated protection and reversed Akap12 mRNA and protein levels cortical-derived ECs. Direct stimulation of Tie2 using Vasculotide, angiopoietin-1 memetic peptide, phenocopied the neuroprotection. Finally, we report a noteworthy rise in soluble Ang2 in the sera of individuals with acute TBI, highlighting its promising role as a vascular biomarker for early detection of BBB disruption. These findings describe a contribution of the axon guidance molecule, EphA4, in mediating TBI microvascular dysfunction through negative regulation of Tie2/Akap12 signaling.

Low power consumption grating magneto-optical trap based on planar elements.

The grating-based magneto-optical trap (GMOT) is a promising approach for miniaturizing cold-atom systems. However, the power consumption of a GMOT system dominates its feasibility in practical applications. In this study, we demonstrated a GMOT system based on planar elements that can operate with low power consumption. A high-diffraction-efficiency grating chip was used to cool atoms with a single incident beam. A planar coil chip was designed and fabricated with a low power consumption nested architecture. The grating and coil chips were adapted to a passive pump vacuum chamber, and up to 106 87Rb atoms were trapped. These elements effectively reduce the power consumption of the GMOT and have great potential for applications in practical cold-atom-based devices.

Fragile Treg cells: Traitors in immune homeostasis?

Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.

Prenatally Diagnosed Congenital Oral Teratoma Successfully Treated in a Neonate.

Teratomas are congenital malformations that rarely occur in the oral cavity. In the case reported here, fetal magnetic resonance imaging performed at 30 weeks of gestation informed the decision-making of the multidisciplinary management team, who closely followed the pregnancy until the scheduled cesarean delivery at 38 weeks of gestation. After delivery, tracheal intubation was performed to ensure airway patency, and tumor resection was scheduled immediately after ruling out contraindications to surgery based on preoperative examinations, allowing for safe excising of the tumor. Postoperative follow-up at 3 months showed no abnormalities.

Artificial liver support systems for hepatitis B virus-associated acute-on-chronic liver failure: A meta-analysis of the clinical literature.

To evaluate the short-term and long-term survival efficacy of an artificial liver support system (ALSS) in patients with acute-on-chronic liver failure (ACLF). A systematic search was performed for relevant published data in PubMed, Web of Science and Cochrane Library databases. Studies that evaluated the efficacy of ALSS in patients with ACLF and provided the short-term or long-term survival rate were included. A total of 10 studies involving 3685 patients were included in this analysis. The pooled 28-day survival rate and 90-day survival rate were 68.7% (95% CI: 64.5%-72.9%) and 53.4% (95% CI: 45.5%-61.4%), respectively. The pooled estimates of the OR for the 28-day and 90-day survival rates between the ALSS group and the control group were 1.91 (95% CI: 1.21-3.04) and 1.41 (95% CI: 1.17-1.70), respectively. Subgroup analysis showed that patients treated with lower levels of TBIL and MELD scores had a higher 28-day survival rate (χ2  = 15.75, p < 0.01; χ2  = 13.80, p < 0.01). The present meta-analysis suggests that ALSS treatment could remarkably improve short-term survival rates in HBV-ACLF patients, which implies that treatment with ALSS may help to reduce high mortality. Further prospective randomized trials are needed to validate these findings.

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2 S donor conjugate, complexed with Fe2+ , termed AAN-PTC-Fe2+ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2 S, an inhibitor of catalase, an enzyme that detoxifies H2 O2 . Fe2+ and H2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+ , the AAN sequence, or the ability to generate H2 S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.

Deferasirox shows inhibition activity against cervical cancer in vitro and in vivo.

OBJECTIVE: Iron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. METHODS: In this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. RESULTS: The cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. CONCLUSION: Present study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.

The Role of SBI2/ALG12/EBS4 in the Regulation of Endoplasmic Reticulum-Associated Degradation (ERAD) Studied by a Null Allele.

Redundancy and lethality is a long-standing problem in genetics but generating minimal and lethal phenotypes in the knockouts of the same gene by different approaches drives this problem to a new high. In Asn (N)-linked glycosylation, a complex and ubiquitous cotranslational and post-translational protein modification required for the transfer of correctly folded proteins and endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins, ALG12 (EBS4) is an α 1, 6-mannosyltransferase catalyzing a mannose into Glc3Man9GlcNAc2. In Arabidopsis, T-DNA knockout alg12-T is lethal while likely ebs4 null mutants isolated by forward genetics are most healthy as weak alleles, perplexing researchers and demanding further investigations. Here, we isolated a true null allele, sbi2, with the W258Stop mutation in ALG12/EBS4. sbi2 restored the sensitivity of brassinosteroid receptor mutants bri1-5, bri1-9, and bri1-235 with ER-trapped BRI1 to brassinosteroids. Furthermore, sbi2 maturated earlier than the wild-type. Moreover, concomitant with impaired and misfolded proteins accumulated in the ER, sbi2 had higher sensitivity to tunicamycin and salt than the wild-type. Our findings thus clarify the role of SBI2/ALG12/EBS4 in the regulation of the ERAD of misfolded glycoproteins, and plant growth and stress response. Further, our study advocates the necessity and importance of using multiple approaches to validate genetics study.

Clioquinol Attenuates Pulmonary Fibrosis through Inactivation of Fibroblasts via Iron Chelation.

Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.

Effect of Crosslinker Topology on Enzymatic Degradation of Hydrogels.

Despite the widespread use of hydrogels in biomedical applications, little is known regarding the effect of crosslinker topology on hydrogel degradation. Dendritic and linear elastin-like peptides (ELPs) were used as crosslinkers for hyaluronic acid (HA) hydrogels, and their enzymatic degradation was studied using trypsin. Rheological studies revealed that hydrogels crosslinked with ELP dendrimers (HA_denELPs) degraded more slowly than those crosslinked with the otherwise equivalent linear ELPs (i.e., both molecules have the same number of pentamers and peripheral lysine residues). The origin of this phenomenon was evaluated using solution studies in which various dendritic and linear ELPs were treated with trypsin. Apart from the expected steric hindrances due to the dendritic topology, we identified the dual directionality of the peptide sequences (generated by a central branching lysine residue) and the likelihood of cleaving a productive crosslinking point as two additional contributors to the lesser degradability of HA_denELPs. Overall, these results highlight how the molecular design of crosslinker topology represents a novel strategy to tune the degradation rate of hydrogels.

Diels-Alder/Ene Reactivities of 2-(1'-Cycloalkenyl)thiophenes and 2-(1'-Cycloalkenyl)benzo[b]thiophenes with N-Phenylmaleimides: Role of Cycloalkene Ring Size on Benzothiophene and Dibenzothiophene Product Distributions.

Scaffolds of thiophene and benzothiophene are the important class of bioactive compounds found abundant in nature. The Diels-Alder reactions of 2-(1'-cycloalkenyl)thiophenes and 2-(1'-cycloalkenyl)benzo[b]thiophenes having the alkene groups present in five-, six-, seven-, eight-, and twelve-membered rings with substituted N-phenylmaleimides are characterized. The size of the cycloalkene rings plays a critical role in dictating the product distributions of expected and isomerized Diels-Alder adducts. 2D NMR studies indicate that the isolated isomers for 2-(1'-cycloalkenyl)thiophenes having five-, six-, and seven-membered rings are aromatized benzothiophene products, whereas eight- and twelve-membered rings are un-rearranged adducts. In addition, the product of subsequent ene-reaction with the N-phenylmaleimide is isolated for the five- and six-membered ring cases. Interestingly, in the 2-(1'-cycloalkenyl)benzo[b]thiophene having five-, six-, seven-, eight-, and twelve-membered rings, the un-rearranged dibenzothiophene Diels-Alder adduct is isolated in every instance. Molecular mechanics and density functional theory (M06-2X and PBE0-D3) calculations are performed to understand the differential reactivity of the various dienes for both the initial Diels-Alder reaction and a possible, subsequent ene reaction.

Comparative Transcriptome Analysis of Two Aegilops tauschii with Contrasting Drought Tolerance by RNA-Seq.

As the diploid progenitor of common wheat, Aegilops tauschii is considered to be a valuable resistance source to various biotic and abiotic stresses. However, little has been reported concerning the molecular mechanism of drought tolerance in Ae. tauschii. In this work, the drought tolerance of 155 Ae. tauschii accessions was firstly screened on the basis of their coleoptile lengths under simulated drought stress. Subsequently, two accessions (XJ002 and XJ098) with contrasting coleoptile lengths were selected and intensively analyzed on rate of water loss (RWL) as well as physiological characters, confirming the difference in drought tolerance at the seedling stage. Further, RNA-seq was utilized for global transcriptome profiling of the two accessions seedling leaves under drought stress conditions. A total of 6969 differentially expressed genes (DEGs) associated with drought tolerance were identified, and their functional annotations demonstrated that the stress response was mediated by pathways involving alpha-linolenic acid metabolism, starch and sucrose metabolism, peroxisome, mitogen-activated protein kinase (MAPK) signaling, carbon fixation in photosynthetic organisms, and glycerophospholipid metabolism. In addition, DEGs with obvious differences between the two accessions were intensively analyzed, indicating that the expression level of DEGs was basically in alignment with the physiological changes of Ae. tauschii under drought stress. The results not only shed fundamental light on the regulatory process of drought tolerance in Ae. tauschii, but also provide a new gene resource for improving the drought tolerance of common wheat.

A novel antibody-drug conjugate, HcHAb18-DM1, has potent anti-tumor activity against human non-small cell lung cancer.

Cluster of differentiation 147 (CD147), a transmembrane protein of the immunoglobulin superfamily, is a potential target of treatment against human non-small cell lung cancer (NSCLC). Although there have been exciting advances in epidermal growth factor receptor (EGFR)-targeted therapy for NSCLC in recent years, additional novel targeted agents are needed to improve the efficiency and to offer more options for patients. Antibody-drug conjugates (ADCs) utilize a chemical linker to conjugate cytotoxic drugs to a monoclonal antibody to maximize the delivery to target cells and minimize the delivery to other normal cells. The aim of this study was to prepare a novel anti-CD147 conjugate and examine the tumoricidal effect on NSCLC in vitro and in vivo. HcHAb18 was conjugated to the drug maytansinoid 1 (DM1) via a non-cleavable thioether linker (SMCC) to prepare HcHAb18-DM1 with an appropriate drug-antibody ratio (DAR). NSCLC cell lines expressing different levels of CD147 were tested in vitro to determine internalization, cell cycle arrest and cytotoxicity. In vivo efficacy and safety of HcHAb18-DM1 were evaluated in NSCLC xenograft mouse models. We found that HcHAb18-DM1 displayed an impressive potency in vitro and in vivo with a favorable safety profile. Upon binding to CD147, HcHAb18 could be internalized and delivered the payload DM1 to disturb mitotic spindle formation by microtubules. Target cells were arrested at G2/M phase and HcHAb18-DM1 exerted antiproliferative activity in vitro. Antigen-antibody binding and target cells with high growth rate were two integral prerequisites for exerting anti-tumor activity of HcHAb18-DM1. Therefore, we suggest HcHAb18-DM1 is a promising CD147-targeted therapeutic for NSCLC.

[Ferroptosis inducer IKE ameliorate pulmonary fibrosis in collagen-induced arthritis (CIA) mice via decreasing the expression of IL-6, CCL5 and CXCL9].

Objective To investigate the impact of imidazole ketone erastin (IKE), a ferroptosis inducer, on pulmonary fibrosis progression in mice with collagen-induced arthritis (CIA), and to understand its potential mechanism. Methods Chick type II collagen emulsified in complete Freund's adjuvant (CFA) was injected into DBA/1 mice, aged 8 to 10 weeks, to induce CIA. Fourteen days later, type II collagen emulsified in incomplete Freund's adjuvant (IFA) was administered to the mice. The mice were randomly divided into a control group, a CIA group and a CIA combined IKE group. The development of arthritis was monitored by evaluating the arthritis scores every two days until day 39 and then the mice were sacrificed for organ collection. The histopathological changes of joints were evaluated by HE staining, Safranin O-fast green staining and toluidine blue staining. The histopathological changes of organs including heart, liver, spleen, lung, and kidney were evaluated by HE staining, and Masson's trichrome staining was used to assess pulmonary fibrosis. The expression levels of smooth muscle actin α (α-SMA), fibroblast activating protein α (FAPα), transforming growth factor ß (TGF-ß), type I collagen (Col1), interleukin 1(IL-1), IL-6, IL-17 and tumor necrosis factor α (TNF-α) were detected by immunohistochemical staining. The expression levels of serum cytokines including IL-17α, IL-17F, TGF-ß1, ITG-ß6, TNF receptor superfamily menber 11B(TNFRSF11B), TNFRSF12A, IL-6, IL-1α, IL-1ß, IL-10, TNF-α, CCL5, CCL2, CXCL9, CXCL1, NADK, EPO, CSF2, TGF-α, CCL20 and CCL3 in serum were detected by Olink mouse exploratory panel. Results Histological staining in the CIA mice administered with IKE model demonstrated that IKE treatment reduced bone absorption and the degree of synovial inflammation when active inflammation was present. CIA mice administered with IKE showed lower expression levels of α-SMA, FAPα, TGF-ß, Col1, IL-1, IL-6, IL-17 and TNF-α, according to the immunohistochemical staining of the lung. In addition, the expression levels of CCL5, CXCL9 and IL-6 were also decreased in serum of CIA mice treated with IKE. Conclusion IKE not only ameliorates joint inflammation and bone damage, but also alleviates the inflammation and the progression of pulmonary fibrosis in CIA mice.

CircMALAT1 promotes cancer stem-like properties and chemoresistance via regulating Musashi-2/c-Myc axis in esophageal squamous cell carcinoma.

The primary challenge in treating esophageal squamous cell carcinoma (ESCC) is resistance to chemotherapy. Cancer stem cell (CSC) is the root cause of tumor drug resistance. Therefore, targeting CSCs has been considered promising therapeutic strategy for tumor treatment. Here, we report that circMALAT1 was significantly upregulated in ESCC CSC-like cells and primary tumors from ESCC patients. Clinically, there was a positive correlation between circMALAT1 expression and ESCC stage and lymph node metastasis, as well as poor prognosis for ESCC patients. In vitro and in vivo functional studies revealed that circMALAT1 promoted CSC-like cells expansion, tumor growth, lung metastasis and drug resistance of ESCC. Mechanistically, circMALAT1 directly interacted with CSC-functional protein Musashi RNA Binding Protein 2 (MSI2). CircMALAT1 inhibited MSI2 ubiquitination by preventing it from interacting with ß-transducin repeat containing protein (BTRC) E3 ubiquitin ligase. Also, circMALAT1 knockdown inhibited the expression of MSI2-regulating CSC-markers c-Myc in ESCC. Collectively, circMALAT1 modulated the ubiquitination and degradation of the MSI2 protein signaling with ESCC CSCs and accelerated malignant progression of ESCC. CircMALAT1 has the potential to serve as a biomarker for drug resistance and as a target for therapy in CSCs within ESCC.

Design, Synthesis, and Antifungal Activity of 3-Substituted-2(5H)-Oxaboroles.

Next generation antimicrobial therapeutics are desperately needed as new pathogens with multiple resistance mechanisms continually emerge. Two oxaboroles, tavaborole and crisaborole, were recently approved as topical treatments for onychomycosis and atopic dermatitis, respectively, warranting further studies into this privileged structural class. Herein, we report the antimicrobial properties of 3-substituted-2(5H)-oxaboroles, an unstudied family of medicinally relevant oxaboroles. Our results revealed minimum inhibitory concentrations as low as 6.25 and 5.20 µg/mL against fungal (e.g., Penicillium chrysogenum) and yeast (Saccharomyces cerevisiae) pathogens, respectively. These oxaboroles were nonhemolytic and nontoxic to rat myoblast cells (H9c2). Structure-activity relationship studies suggest that planarity is important for antimicrobial activity, possibly due to the effects of extended conjugation between the oxaborole and benzene rings.

Characterization of two novel hydrolases from Sphingopyxis sp. DBS4 for enantioselective degradation of chiral herbicide diclofop-methyl.

Diclofop-methyl, an aryloxyphenoxypropionate (AOPP) herbicide, is a chiral compound with two enantiomers. Microbial detoxification and degradation of various enantiomers is garnering immense research attention. However, enantioselective catabolism of diclofop-methyl has been rarely explored, especially at the molecular level. This study cloned two novel hydrolase genes (dcmA and dcmH) in Sphingopyxis sp. DBS4, and characterized them for diclofop-methyl degradation. DcmA, a member of the amidase superfamily, exhibits 26.1-45.9% identity with functional amidases. Conversely, DcmH corresponded to the DUF3089 domain-containing protein family (a family with unknown function), sharing no significant similarity with other biochemically characterized proteins. DcmA exhibited a broad spectrum of substrates, with preferential hydrolyzation of (R)-(+)-diclofop-methyl, (R)-(+)-quizalofop-ethyl, and (R)-(+)-haloxyfop-methyl. DcmH also preferred (R)-(+)-quizalofop-ethyl and (R)-(+)-haloxyfop-methyl degradation while displaying no apparent enantioselective activity towards diclofop-methyl. Using site-directed mutagenesis and molecular docking, it was determined that Ser175 was the fundamental residue influencing DcmA's activity against the two enantiomers of diclofop-methyl. For the degradation of AOPP herbicides, DcmA is an enantioselective amidase that has never been reported in research. This study provided novel hydrolyzing enzyme resources for the remediation of diclofop-methyl in the environment and deepened the understanding of enantioselective degradation of chiral AOPP herbicides mediated by microbes.

Targeted regulated cell death with small molecule compounds in colorectal cancer: Current perspectives of targeted therapy and molecular mechanisms.

Colorectal cancer (CRC), a tumor of the digestive system, is characterized by high malignancy and poor prognosis. Currently, targeted therapy of CRC is far away from satisfying. The molecular mechanisms of regulated cell death (RCD) have been clearly elucidated, which can be intervened by drug or genetic modification. Numerous studies have provided substantial evidence linking these mechanisms to the progression and treatment of CRC. The RCD includes apoptosis, autophagy-dependent cell death (ADCD), ferroptosis, necroptosis, and pyroptosis, and immunogenic cell death, etc, which provide potential targets for anti-cancer treatment. For the last several years, small-molecule compounds targeting RCD have been a well concerned therapeutic strategy for CRC. This present review aims to describe the function of small-molecule compounds in the targeted therapy of CRC via targeting apoptosis, ADCD, ferroptosis, necroptosis, immunogenic dell death and pyroptosis, and their mechanisms. In addition, we prospect the application of newly discovered cuproptosis and disulfidptosis in CRC. Our review may provide references for the targeted therapy of CRC using small-molecule compounds targeting RCD, including the potential targets and candidate compounds.

CD147-K148me2-Driven Tumor Cell-Macrophage Crosstalk Provokes NSCLC Immunosuppression via the CCL5/CCR5 Axis.

Immunosuppression is a major hallmark of tumor progression in non-small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro-tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di-methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di-methylation of CD147 at Lys148 (CD147-K148me2) is identified as a common post-translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147-K148me2. Further analysis demonstrates that CD147-K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38-ZBTB32 signaling, leading to increased NSCLC cell-derived CCL5 secretion. Subsequently, CD147-K148me2-mediated CCL5 upregulation facilitates M2-like tumor-associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis-dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147-K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147-K148me2-driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM-targeted NSCLC therapy.