类器官技术在肺癌精准治疗中的创新应用与挑战

doi:10.3760/cma.j.cn371439-20250408-00059

摘要/Abstract

摘要：

肺癌类器官通过3D模拟肿瘤微环境，结合CRISPR/Cas9基因编辑与多细胞共培养技术，精准再现原始肿瘤的遗传异质性与病理特征，展现出广阔的应用前景。在临床转化中，其已应用于药物敏感性检测（如逆转铂类耐药）及疗效预测，推动个体化诊疗精准化；同时加速靶向药物研发（如WEE1抑制剂协同免疫治疗）与耐药机制解析。尽管面临样本获取受限、模型标准化不足等挑战，肺癌类器官在揭示预后标志物（如IRAK1BP1）及优化免疫治疗策略中的潜力，仍为肺癌精准诊疗提供了突破性研究路径。

关键词: 肺肿瘤, 类器官, 诊断, 治疗

Abstract:

Lung cancer organoids accurately reproduce the genetic heterogeneity and pathological features of the original tumor by 3D simulation of the tumor microenvironment and combining with CRISPR/Cas9 gene editing and multi-cell co-culture technology，thus demonstrating broad application prospects. In clinical transformation，they have been used for drug sensitivity testing（such as reversing platinum resistance）and efficacy prediction，promoting the precision of individualized diagnosis and treatment. At the same time，they have accelerated the research and development of targeted drugs（such as WEE1 inhibitors in combination with immunotherapy）and the analysis of drug resistance mechanisms. Despite challenges such as limited sample acquisition and insufficient model standardization，the potential of lung cancer organoids in revealing prognostic markers（such as IRAK1BP1）and optimizing immunotherapy strategies still provides a breakthrough research path for the precise diagnosis and treatment of lung cancer.

Key words: Lung neoplasms, Organoids, Diagnosis, Therapy

周黛妍, 曾欣欣, 郝梦迪, 刘维璐, 谢沛, 张绪慧. 类器官技术在肺癌精准治疗中的创新应用与挑战[J]. 国际肿瘤学杂志, 2026, 53(6): 366-369.

Zhou Daiyan, Zeng Xinxin, Hao Mengdi, Liu Weilu, Xie Pei, Zhang Xuhui. Innovative applications and challenges of organoid technology in the precision treatment of lung cancer[J]. Journal of International Oncology, 2026, 53(6): 366-369.

参考文献 39

[1]	Smolarz B, Łukasiewicz H, Samulak D, et al. Lung cancer-pathogenesis, treatment and molecular aspect (review of literature)[J]. Int J Mol Sci, 2025, 26(5): 2049. DOI: 10.3390/ijms26052049.
[2]	Marshall HM, Fong KM. Lung cancer screening-time for an update?[J]. Lung Cancer, 2024, 196: 107956. DOI: 10.1016/j.lungcan.2024.107956.
[3]	Zhang YM, Hu QF, Pei YQ, et al. A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments[J]. Nat Commun, 2024, 15(1): 3382. DOI: 10.1038/s41467-024-47737-z. pmid: 38643164
[4]	Polak R, Zhang ET, Kuo CJ. Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment[J]. Nat Rev Cancer, 2024, 24(8): 523-539. DOI: 10.1038/s41568-024-00706-6. pmid: 38977835
[5]	Peng TP, Ma XJ, Hua W, et al. Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy[J]. Cell Stem Cell, 2025, 32(4): 652-669.e11. DOI: 10.1016/j.stem.2025.01.002.
[6]	Wang J, Wang FX, Jiang YY, et al. Organoid-driven nanomedicine platform development[J]. Biomaterials, 2025, 325: 123611. DOI: 10.1016/j.biomaterials.2025.123611.
[7]	Joo H, Min S, Cho SW. Advanced lung organoids for respiratory system and pulmonary disease modeling[J]. J Tissue Eng, 2024, 15: 20417314241232502. DOI: 10.1177/20417314241232502.
[8]	Jeong SR, Kang MY. Exploring tumor-immune interactions in co-culture models of T cells and tumor organoids derived from patients[J]. Int J Mol Sci, 2023, 24(19): 14609. DOI: 10.3390/ijms241914609.
[9]	Subtil B, Iyer KK, Poel D, et al. Dendritic cell phenotype and function in a 3D co-culture model of patient-derived metastatic colorectal cancer organoids[J]. Front Immunol, 2023, 14: 1105244. DOI: 10.3389/fimmu.2023.1105244.
[10]	Li KY, Liu C, Sui XZ, et al. An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer[J]. Cell Stem Cell, 2025, 32(8): 1218-1234.e7. DOI: 10.1016/j.stem.2025.05.011.
[11]	Gerasimova E, Beenen AC, Kachkin D, et al. Novel co-culture model of T cells and midbrain organoids for investigating neurodegeneration in parkinson's disease[J]. NPJ Parkinsons Dis, 2025, 11(1): 36. DOI: 10.1038/s41531-025-00882-8. pmid: 40021643
[12]	Mircetic J, Camgöz A, Abohawya M, et al. Crispr/Cas9 screen in gastric cancer patient-derived organoids reveals KDM1A-NDRG1 axis as a targetable vulnerability[J]. Small Methods, 2023, 7(6): e2201605. DOI: 10.1002/smtd.202201605.
[13]	Perdigão PRL, Ollington B, Sai H, et al. Retinal organoids from an aipl1 Crispr/Cas9 knockout cell line successfully recapitulate the molecular features of LCA4 disease[J]. Int J Mol Sci, 2023, 24(6): 5912. DOI: 10.3390/ijms24065912.
[14]	Chan DKH, Collins SD, Buczacki SJA. Generation and immunofluorescent validation of gene knockouts in adult human colonic organoids using multi-guide RNA CRISPR-Cas9[J]. STAR Protoc, 2023, 4(1): 101978. DOI: 10.1016/j.xpro.2022.101978.
[15]	Hai J, Zhang H, Zhou J, et al. Generation of genetically engineered mouse lung organoid models for squamous cell lung cancers allows for the study of combinatorial immunotherapy[J]. Clin Cancer Res, 2020, 26(13): 3431-3442. DOI: 10.1158/1078-0432.CCR-19-1627. pmid: 32209571
[16]	Du Y, Wang YR, Bao QY, et al. Personalized vascularized tumor organoid-on-a-chip for tumor metastasis and therapeutic targeting assessment[J]. Adv Materials, 2024, 37(6): e2412815. DOI: 10.1002/adma.202412815.
[17]	Yu TT, Yang QH, Peng B, et al. Vascularized organoid-on-a-chip: design, imaging, and analysis[J]. Angiogenesis, 2024, 27(2): 147-172. DOI: 10.1007/s10456-024-09905-z.
[18]	Zheng MJ, Erice E, Wang HY, et al. Organoid-on-a-chip (orgoc): advancing cystic fibrosis research[J]. Mater Today Bio, 2025, 34: 102148. DOI: 10.1016/j.mtbio.2025.102148.
[19]	Lee E, Lee SY, Seong YJ, et al. Lung cancer organoid-based drug evaluation models and new drug development application trends[J]. Transl Lung Cancer Res, 2024, 13(12): 3741-3763. DOI: 10.21037/tlcr-24-603.
[20]	Xu HX, Jiao DC, Liu A, et al. Tumor organoids: applications in cancer modeling and potentials in precision medicine[J]. J Hematol Oncol, 2022, 15(1): 58. DOI: 10.1186/s13045-022-01278-4.
[21]	Kopper O, De Witte CJ, Lõhmussaar K, et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity[J]. Nat Med, 2019, 25(5): 838-849. DOI: 10.1038/s41591-019-0422-6. pmid: 31011202
[22]	Hu YW, Sui XZ, Song F, et al. Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week[J]. Nat Commun, 2021, 12(1): 2581. DOI: 10.1038/s41467-021-22676-1. pmid: 33972544
[23]	Li HF, Zhang YS, Lan XM, et al. Halofuginone sensitizes lung cancer organoids to cisplatin via suppressing PI3K/Akt and mapk signaling pathways[J]. Front Cell Dev Biol, 2021, 9: 773048. DOI: 10.3389/fcell.2021.773048.
[24]	Tong XY, Patel AS, Kim E, et al. Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer[J]. Cancer Cell, 2024, 42(3): 413-428.e7. DOI: 10.1016/j.ccell.2024.01.012.
[25]	Chen JH, Chu XP, Zhang JT, et al. Genomic characteristics and drug screening among organoids derived from non-small cell lung cancer patients[J]. Thorac Cancer, 2020, 11(8): 2279-2290. DOI: 10.1111/1759-7714.13542.
[26]	Wang Y, Jiang T, Qin Z, et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib[J]. Ann Oncol, 2019, 30(3): 447-455. DOI: 10.1093/annonc/mdy542. pmid: 30596880
[27]	Parikh AY, Masi R, Gasmi B, et al. Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens[J]. Cancer Immunol Immunother, 2023, 72(10): 3149-3162. DOI: 10.1007/s00262-023-03476-6.
[28]	Peng KC, Su JW, Xie Z, et al. Clinical outcomes of EGFR⁺/METAMP⁺ vs. EGFR⁺/METAMP^- untreated patients with advanced non-small cell lung cancer[J]. Thorac Cancer, 2022, 13(11): 1619-1630. DOI: 10.1111/1759-7714.14429.
[29]	Paleari L. Personalized assessment for cancer prevention, detection, and treatment[J]. Int J Mol Sci, 2024, 25(15): 8140. DOI: 10.3390/ijms25158140.
[30]	Zhou Y, Tao L, Qiu JH, et al. Tumor biomarkers for diagnosis, prognosis and targeted therapy[J]. Signal Transduct Target Ther, 2024, 9: 132. DOI: 10.1038/s41392-024-01823-2.
[31]	Guo L, Zhou WP, Xu ZW, et al. Identification of IRAK1BP1 as a candidate prognostic factor in lung adenocarcinoma[J]. Front Oncol, 2023, 13: 1132811. DOI: 10.3389/fonc.2023.1132811.
[32]	Liu T, Guo W, Luo K, et al. Smoke-induced SAV1 gene promoter hypermethylation disrupts YAP negative feedback and promotes malignant progression of non-small cell lung cancer[J]. Int J Biol Sci, 2022, 18(11): 4497-4512. DOI: 10.7150/ijbs.73428. pmid: 35864957
[33]	Juan LS, Freije A, Sanz-Gómez N, et al. DNA damage triggers squamous metaplasia in human lung and mammary cells via mitotic checkpoints[J]. Cell Death Discov, 2023, 9(1): 21. DOI: 10.1038/s41420-023-01330-3. pmid: 36681661
[34]	Qu FF, Brough SC, Michno W, et al. Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis[J]. Nat Cell Biol, 2023, 25(10): 1506-1519. DOI: 10.1038/s41556-023-01241-6. pmid: 37783795
[35]	Wang HM, Zhang CY, Peng KC, et al. Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: a real-world study[J]. Cell Rep Med, 2023, 4(2): 100911. DOI: 10.1016/j.xcrm.2022.100911.
[36]	Dijkstra KK, Monkhorst K, Schipper LJ, et al. Challenges in establishing pure lung cancer organoids limit their utility for personalized medicine[J]. Cell Rep, 2020, 31(5): 107588. DOI: 10.1016/j.celrep.2020.107588.
[37]	Wu F, Fan J, He Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer[J]. Nat Commun, 2021, 12(1): 2540. DOI: 10.1038/s41467-021-22801-0. pmid: 33953163
[38]	Sutherland TE, Dyer DP, Allen JE. The extracellular matrix and the immune system: a mutually dependent relationship[J]. Science, 2023, 379(6633): eabp8964. DOI: 10.1126/science.abp8964.
[39]	Monleón-Guinot I, Milian L, Martínez-Vallejo P, et al. Morphological characterization of human lung cancer organoids cultured in type Ⅰ collagen hydrogels: a histological approach[J]. Int J Mol Sci, 2023, 24(12): 10131. DOI: 10.3390/ijms241210131.