2. Academic Validation
  3. Optimized patient-derived lung cancer organoids recapitulating the immune landscape for precision therapy evaluation

Optimized patient-derived lung cancer organoids recapitulating the immune landscape for precision therapy evaluation

  • Cell Oncol (Dordr). 2026 Jan 6;49(1):15. doi: 10.1007/s13402-025-01158-2.
Huayang Xing # 1 2,  Rui Liu # 1,  Yidan Chen # 1,  Xueqin Chen 3 4 5,  Xianzhi Gao 6,  Chongyang Shen 7,  Shirong Zhang 8,  Yi Tang 3,  Longfeng Wu 9,  Mingliang You 10,  Pinglong Xu 11,  Bing Xia 12
Affiliations

Affiliations

  • 1 Hangzhou Cancer Institute, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
  • 2 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 61000, China.
  • 3 Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China.
  • 4 School of Medicine, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, 310006, China.
  • 5 Fourth Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, 310053, China.
  • 6 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • 7 Basic Medicine School, Chengdu University of Traditional Chinese Medicine, Chengdu, 61000, China.
  • 8 Translational Medicine Research Center, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, 310006, China.
  • 9 Department of Thoracic Surgery, Hangzhou Cancer Hospital, 310002, Hangzhou, China.
  • 10 Hangzhou Cancer Institute, Hangzhou Cancer Hospital, Hangzhou, 310002, China. [email protected].
  • 11 Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 12 Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China. [email protected].
  • # Contributed equally.
PMID: 41493730 DOI: 10.1007/s13402-025-01158-2
Abstract

Purpose: Current lung cancer Organoid models often fail to replicate the complex tumor immune microenvironment, reducing their predictive value for immunotherapy and radiotherapy. Therefore, it is crucial to establish an optimized lung cancer Organoid model which could recapitulate the tumor immune microenvironment, enabling more accurate evaluation of therapeutic responses.

Methods: We developed an optimized air-liquid interface (ALI) culture method to generate patient-derived lung Cancer organoids (ALI-LUOs) from 19 lung Cancer samples. The tumor microenvironment, including immune and stromal components, was characterized using immunofluorescence, flow cytometry, and single-cell RNA Sequencing. The organoids were further used to assess responses to αPD-1 therapy and radiotherapy.

Results: The optimized method significantly improved Organoid formation efficiency while preserving immune cell viability for up to 30 days. Immune and fibroblast populations were confirmed by immunofluorescence and flow cytometry. Single-cell RNA Sequencing demonstrated that ALI-LUOs accurately replicate the tumor immune landscape. Key tumor immunity pathways such as cGAS-STING could be captured by ALI-LUOs. Importantly, ALI-LUOs modeled clinical responses to immune checkpoint inhibitors and radiotherapy with high fidelity.

Conclusions: The ALI-LUOs, developed through an optimized culture method, faithfully capture the key characteristics of lung Cancer, including its immunosuppressive tumor microenvironment. Our findings highlight this modified ALI-LUOs as a valuable preclinical platform for evaluating antitumor immunity and refining lung Cancer treatments.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13402-025-01158-2.

Keywords

Air-liquid interface culture; Immunotherapy; Lung cancer; Patient-derived organoids; Radiotherapy response; Single-cell RNA sequencing.

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