Dissecting Macrophage Heterogeneity and Kaempferol in Lung Adenocarcinoma: a Single-cell Transcriptomic Approach and Network Pharmacology

Overview

Journal Discov Oncol

Publisher Springer

Date 2025 Jan 30

PMID 39884998

Authors

Laiyi Wan

Wentao Hao

Leilei Li

Lin Wang

Yanzheng Song

Affiliations

Soon will be listed here.

Abstract

Background: Lung adenocarcinoma (LUAD) is a leading form of non-small cell lung cancer characterized by a complex tumor microenvironment (TME) that influences disease progression and therapeutic response. Tumor-associated macrophages (TAMs) within the TME promote tumorigenesis and evasion of immune surveillance, though their heterogeneity poses challenges in understanding their roles and therapeutic targeting. Additionally, traditional Chinese medicine (TCM) offers potential anti-cancer agents that could modulate the immune landscape.

Methods: We conducted single-cell RNA sequencing (scRNA-seq) on LUAD samples, performing an in-depth analysis of macrophage populations and their expression signatures. Network pharmacology was used to identify TCM components with potential TAM-modulatory effects, focusing on Astragalus membranaceus. Pseudotime trajectory analysis, immunofluorescence staining, and in vitro assays examined the functional roles of TAMs and the effects of selected compounds on macrophage polarization.

Results: Our scRNA-seq analysis identified notable heterogeneity among macrophages, revealing predominant M2-like phenotypes within TAMs. Network pharmacology highlighted active TCM ingredients, including quercetin, isorhamnetin, and kaempferol, targeting genes related to macrophage function. Survival analysis implicated AHSA1, CYP1B1, SPP1, and STAT1 as prognostically significant factors. Further experiments demonstrated kaempferol's efficacy in inhibiting M2 polarization, underlining a selective influence on TAM functionality.

Conclusions: This study delineates the diverse macrophage landscape in LUAD and suggests a pivotal role for STAT1 in TAM-mediated immunosuppression. Kaempferol, identified from TCM, emerges as an influential agent capable of altering TAM polarization, potentially enhancing anti-tumoral immunity. These findings underscore the translational potential of integrating TCM-derived compounds into immunotherapeutic strategies for LUAD.

References

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

Jia W, Liang S, Jin M, Li S, Yuan J, Zhang J . Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling. Phytomedicine. 2024; 126:155208. DOI: 10.1016/j.phymed.2023.155208. View

Meng B, Zhao N, Mlcochova P, Ferreira I, Ortmann B, Davis T . Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry. Cell Rep. 2024; 43(7):114471. DOI: 10.1016/j.celrep.2024.114471. View

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

Fu J, Wang Z, Huang L, Zheng S, Wang D, Chen S . Review of the botanical characteristics, phytochemistry, and pharmacology of Astragalus membranaceus (Huangqi). Phytother Res. 2014; 28(9):1275-83. DOI: 10.1002/ptr.5188. View

Wu F, Wang L, Zhou C . Lung cancer in China: current and prospect. Curr Opin Oncol. 2020; 33(1):40-46. DOI: 10.1097/CCO.0000000000000703. View

Binder A, Bremm F, Dorrie J, Schaft N . Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential. Int J Mol Sci. 2024; 25(13). PMC: 11242727. DOI: 10.3390/ijms25137275. View

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

Ru J, Li P, Wang J, Zhou W, Li B, Huang C . TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014; 6:13. PMC: 4001360. DOI: 10.1186/1758-2946-6-13. View

Argentiero A, Andriano A, Caradonna I, de Martino G, Desantis V . Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions. Cancers (Basel). 2024; 16(13). PMC: 11240778. DOI: 10.3390/cancers16132438. View

10.

Wang X, Xu Y, Sun Q, Zhou X, Ma W, Wu J . New insights from the single-cell level: Tumor associated macrophages heterogeneity and personalized therapy. Biomed Pharmacother. 2022; 153:113343. DOI: 10.1016/j.biopha.2022.113343. View

11.

Salcher S, Sturm G, Horvath L, Untergasser G, Kuempers C, Fotakis G . High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer. Cancer Cell. 2022; 40(12):1503-1520.e8. PMC: 9767679. DOI: 10.1016/j.ccell.2022.10.008. View

12.

Li C, Liu Y, Zhang Y, Li J, Lai J . Astragalus polysaccharide: a review of its immunomodulatory effect. Arch Pharm Res. 2022; 45(6):367-389. DOI: 10.1007/s12272-022-01393-3. View

13.

Chen J, Ma H, Meng Y, Liu Q, Wang Y, Lin Y . Analysis of the mechanism underlying diabetic wound healing acceleration by Calycosin-7-glycoside using network pharmacology and molecular docking. Phytomedicine. 2023; 114:154773. DOI: 10.1016/j.phymed.2023.154773. View

14.

Xiao X, Peng Y, Wang Z, Zhang L, Yang T, Sun Y . A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME. Pharmacol Res. 2022; 181:106269. DOI: 10.1016/j.phrs.2022.106269. View

15.

Hu M, Deng F, Song X, Zhao H, Yan F . The crosstalk between immune cells and tumor pyroptosis: advancing cancer immunotherapy strategies. J Exp Clin Cancer Res. 2024; 43(1):190. PMC: 11234789. DOI: 10.1186/s13046-024-03115-7. View

16.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

17.

Wu F, Fan J, He Y, Xiong A, Yu J, Li Y . Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun. 2021; 12(1):2540. PMC: 8100173. DOI: 10.1038/s41467-021-22801-0. View

18.

Chen L, Chang L, Wu W, Jing M, Li H, Niu C . Multi-omics analysis combined with network pharmacology revealed the mechanisms of rutaecarpine in chronic atrophic gastritis. J Ethnopharmacol. 2024; 339:119151. DOI: 10.1016/j.jep.2024.119151. View

19.

Song Q, Hawkins G, Wudel L, Chou P, Forbes E, Pullikuth A . Dissecting intratumoral myeloid cell plasticity by single cell RNA-seq. Cancer Med. 2019; 8(6):3072-3085. PMC: 6558497. DOI: 10.1002/cam4.2113. View