bims-exocan 2026-07-05 papers

Issue of 2026–07–05
four papers selected by
Muhammad Rizwan, COMSATS University

Anticancer Agents Med Chem. 2026 Jun 24.

Discovery of Serum Exosomal Protein Biomarkers for Early- and Late-Stage Lung Cancer Through Comparative Proteomic Analysis.

Dong Zeng, Xiaoli Huang, Haicheng Tang, Mingsheng Chen, Jingjing Xu, Yuhan Shi, Shu Song.

BACKGROUND: Lung adenocarcinoma (LUAD) exhibits distinct immune microenvironments in early-stage (ES-LUAD), advanced-stage (AS-LUAD), and pneumonia (PNA). Tumor-derived exosomes facilitate intercellular communication and contribute to the development and progression of tumors.
OBJECTIVES: This study aims to comprehensively profile and compare the serum exosomal proteome across ESLUAD, AS-LUAD, and PNA patients, identify differentially expressed exosomal proteins (DEEPs) with potential as stage-specific diagnostic and prognostic biomarkers, and elucidate the biological pathways associated with LUAD progression through functional enrichment analysis of the identified DEEPs.
METHODS: Exosomes were extracted from blood samples and characterized using TEM, NTA, and Western blotting. Proteomic analysis was performed via LC-MS-MS, and differentially expressed genes (DEGs) were analyzed using hierarchical clustering, Gene Ontology (GO), and KEGG pathway analysis.
RESULTS: Distinct exosomal protein signatures were identified across LUAD stages and PNA. CD81 and IGLV7- 46 were identified as potential biomarkers for early detection, staging, and prognosis. GO analysis revealed significant dysregulation in immune response, leukocyte activation, and response to stimuli, with cellular components implicating the extracellular matrix and cell-cell interactions. KEGG analysis highlighted differences in adrenergic signaling.
DISCUSSION: This study aims to comprehensively profile and compare the serum exosomal proteome across ESLUAD, AS-LUAD, and PNA patients; identify differentially expressed exosomal proteins (DEEPs) with potential as stage-specific diagnostic and prognostic biomarkers; and elucidate the biological pathways associated with LUAD progression through functional enrichment analysis of identified DEEPs.
CONCLUSION: Stage-specific serum exosomal protein alterations reflect LUAD biology and show strong potential as non-invasive diagnostic and prognostic biomarkers, advancing understanding and offering tools for early detection and monitoring. Clinical validation is still required.

Keywords: LUAD; bioinformatics analysis; hierarchical clustering.; pneumonia; protein biomarkers; serum exosomes

DOI: https://doi.org/10.2174/0118715206418059250915054635

Clin Transl Med. 2026 Jul;16(7): e70728

Tumour-macrophage crosstalk initiated by NFIC/METTL3 negative feedback loop via exosomal miR-194-5p promotes NSCLC progression.

Shu Fang, Mingyue Hao, Han Meng, Yuhang Jiang, Qiwen Li, Jiao Liang, Xiaolu He, Yi Hu, Linling Zhou, Qianrun Wang, Qiyuan Zhuo, Ji Wu, Kesong Shi.

BACKGROUND: The interplay between tumour cells and tumour-associated macrophages (TAMs) within the tumour microenvironment is crucial for the progression of non-small cell lung cancer (NSCLC). The underlying mechanisms involving RNA modification and exosomal communication remain incompletely understood.
METHODS: Multiplex immunofluorescence and flow cytometry were performed to evaluate M2 macrophage polarization. Exosomes were isolated by ultracentrifugation and validated by transmission electron microscopy, nanoparticle tracking analysis, and exosomal marker blots. To investigate the molecular mechanism, methylated RNA immunoprecipitation (MeRIP)-qPCR and dual-luciferase reporter assays were used to validate m6A modification sites on NFIC and miR-194-5p; RNA immunoprecipitation (RIP) confirmed the interaction between ZNF106 and interleukin-6 (IL-6) mRNA; chromatin immunoprecipitation (ChIP) was employed to detect STAT3 binding to the METTL3 promoter. The in vivo function of the identified feedback loop was assessed using an orthotopic xenograft mouse model of NSCLC.
RESULTS: A negative feedback loop between METTL3 and NFIC was demonstrated in NSCLC cells. METTL3 suppressed miR-194-5p expression and its loading into exosomes through m6A methylation. NSCLC-derived exosomal miR-194-5p was internalized by macrophages and directly targeted ZNF106, thereby inhibiting M2 polarization. In macrophages, ZNF106 stabilized IL-6 mRNA and promoted exosomal IL-6 secretion, thereby activating the JAK2/STAT3 pathway and upregulating METTL3. This IL-6-driven METTL3 upregulation formed a positive feedback loop that sustains M2 polarization and tumour progression. In vivo disruption of this loop reduced tumour growth and metastasis.
CONCLUSIONS: These findings establish a closed regulatory circuit initiated by an NFIC/METTL3 negative feedback loop. In this circuit, METTL3-mediated m6A modification of exosomal miR-194-5p in NSCLC cells derepresses ZNF106 expression in macrophages, leading to IL-6 production that activates the JAK2/STAT3 pathway and upregulates METTL3 in tumour cells, thereby perpetuating M2 polarization and malignant progression. This circuitry offers potential nodes for therapeutic intervention in NSCLC.
KEY POINTS: NFIC/METTL3 negative feedback loop in NSCLC cells suppresses exosomal miR-194-5p via m6A methylation; reduced miR-194-5p deepresses ZNF106 in macrophages, promoting M2 polarization and IL-6 secretion; Macrophage-derived IL-6 activates JAK2/STAT3 in NSCLC cells to upregulate METTL3, forming a positive feedback loop.

Keywords: METTL3; NSCLC; ZNF106; exosome; macrophage polarization; miR‐194‐5p

DOI: https://doi.org/10.1002/ctm2.70728

Discov Oncol. 2026 Jul 02.

Engineered immune cells and extracellular vesicles target tumour microenvironment barriers in solid tumour immunotherapy.

Xiaowei Zhou, Shixin Chen, Junbo Liang.

Adoptive cell therapy (ACT) for solid tumours frequently fails because the tumour microenvironment (TME) imposes multiple, overlapping barriers, including stromal exclusion, suppressive myeloid networks, inhibitory cytokines and metabolites, and antigen heterogeneity. Collectively, these factors markedly restrict the infiltration, persistence, and cytotoxic function of effector lymphocytes. In this Review, we synthesise recent primary studies, consensus guidance, and clinical-trial evidence on engineered-cell therapies, including chimeric antigen receptor (CAR) T cells, T-cell receptor-engineered T cells (TCR-T cells), CAR-NK cells, CAR-macrophages (CAR-M), and emerging in vivo CAR-engineering strategies, together with extracellular-vesicle (EV)-based therapeutics. We then map each platform to mechanism-linked resistance nodes within the TME. For engineered cells, key design levers include context-restricted recognition to reduce on-target/off-tumour toxicity, resistance to dominant suppressive pathways such as TGF-β and adenosine signalling, improved trafficking and tissue penetration, and controllability through transient programming or pharmacological switches. For EVs, the main translational advantages include tissue penetration, modular surface engineering, cargo loading, and their acellular nature, which avoids risks related to in vivo cellular expansion but introduces distinct challenges such as rapid clearance, immunogenicity, batch heterogeneity, and uncertain potency assays. Early clinical data using KRAS G12D-targeting engineered exosomes in metastatic pancreatic cancer support the feasibility of this approach and suggest that EVs may also remodel the immune microenvironment, providing a rationale for combination strategies. We propose a barrier-matched framework in which engineered cells and extracellular vesicles are assigned as functionally orthogonal but complementary modules: engineered cells provide adaptive cytotoxicity, whereas EVs enable microenvironmental reconditioning. This framework may help guide rational combination strategies designed to systematically dismantle resistance in solid tumours.

Keywords: CAR-NK; CAR-T; CAR-macrophage; Engineered exosomes; Extracellular vesicles; Immunotherapy resistance; Solid tumours; Tumour microenvironment

DOI: https://doi.org/10.1007/s12672-026-05523-x

Bioimpacts. 2026 ;16 33180

Targeted delivery of doxorubicin using RSV F-protein modified breast cancer-derived exosomes in breast cancer-bearing mice.

Narges Mardi, Amir Zarebkohan, Cigir Biray-Avci, Reza Rahbarghazi, Mehdi Talebi, Hamid Lotfimehr, Sharareh Khavandkari, Zahra Abbasi-Malati, Nastaran Sedghi-Samarkhazan, Elham Shahriyari, Asghar Khalilnezhad, Morteza Milani, Mohammad Nouri.

Introduction: Triple-negative breast cancer demonstrated high metastasis and mortality rates in female populations. Emerging data on effective targeting and specific internalization of chemotherapeutic agents, using modified exosomes, decreased the therapeutic dosage of anti-cancer drugs in cancer cells.
Methods: Herein, we developed modified exosomes by surface decoration using the Fusion protein of Respiratory Syncytial Virus (F-protein of RSV) through Click-chemistry techniques, and Dox-loaded via sonication strategy. Then, the viability and metastatic behaviors of MDA-MB-231 cells were monitored in the presence of different groups, including Dox, Exosomes (Exo), Exosomes loaded with Dox (Exo@Dox), and F-protein coupled Exosome groups (Exo-F) and (Exo-F@Dox).
Results: In vitro and in vivo results verified that the F-protein coupled exosome, as a modified natural nanoplatform, possessed a biocompatible nature in blood circulation and crossing of blood barriers. After exposure to tumoral temperature (40 °C) and lysosomal PH (5.5) demonstrate amplified Dox release (around 60% at 8 h). Also, in vitro uptake results confirmed a significant increase in Exo-F internalization compared to the Exo group in MDA-MB-231 cells (P<0.0001). Correspondingly, the IC50 value of Exo-F@Dox versus free Dox showed a significant reduction (24-fold more potent) (P<0.0001). Interestingly, Dox-free modified Exo (Exo-F) showed appreciable cytotoxicity (IC50 of about 0.1 µg /mL for exosomal protein concentration) (P˂0.0001). Also, migration assay results confirmed a considerable decrease in the migrated population of MDA-MB-231 cells (10%) compared to the control group, following exposure to modified exosomes. Interestingly, an in vivo study in tumor-bearing Balb/c mice demonstrated a significantly decreased tumor size in the Exo-F groups compared to other formulations.
Conclusion: In summary, F-protein modified exosomes exhibited superior anticancer efficacy by improving tumor-specific targeting, ensuring precise delivery of chemotherapeutic agents, facilitating efficient drug release, and allowing for lower therapeutic dosages.

Keywords: Breast cancer; Fusion protein of RSV; Modified exosomes; Targeted delivery

DOI: https://doi.org/10.34172/bi.33180