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Molecular Diagnostics

Molecular phenotypes stratify small cell lung cancer for targeted therapy and immunotherapy

British Journal of Cancer (2026)Cite this article

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Abstract

Background

Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, exhibits high intertumoral heterogeneity and limited treatment options. Immune checkpoint inhibitors (ICIs) provide only modest benefits for SCLC, underscoring the need for clinically actionable phenotypes.

Methods

Consensus clustering of bulk transcriptomic data identified SCLC molecular phenotypes. Bulk and single-cell RNA sequencing (scRNA-seq) revealed their molecular and immune characteristics, as well as tumor microenvironment interactions. Survival benefits of ICIs were assessed in 41 newly collected extensive-stage SCLC (ES-SCLC) patients treated with chemotherapy plus ICIs, integrated with a public dataset.

Results

We identified three distinct SCLC phenotypes, termed proliferative, iNotch, and infiltrated phenotypes, as they were characterized by high proliferation, inhibitory Notch signaling, and immune-rich microenvironments, respectively. These phenotypes were reproducible across three bulk independent datasets. Further intercellular communication analysis of scRNA-seq data revealed a subset with high ANXA1 expression in the infiltrated phenotype suppressed CD8+ T cells via M2 macrophage polarization. Survival analyses showed that only ANXA1Low infiltrated patients derived significant survival benefit from chemotherapy plus ICIs.

Conclusions

This study identified three distinct SCLC phenotypes with unique therapeutic vulnerabilities. An ANXA1High subset within the immune-rich infiltrated phenotype showed ICI resistance, offering new strategies to enhance ICI efficacy.

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Fig. 1: Consensus clustering of small cell lung cancer (SCLC) samples identifies three phenotypes with distinct molecular and immune features.
Fig. 2: The single-cell transcriptional landscape of SCLC.
Fig. 3: Infiltrated tumors are enriched with conventional dendritic cell 1 (cDC1) and CD8+ cytotoxic T cells (CTL).
Fig. 4: Cell-cell communication atlas among SCLC phenotypes.
Fig. 5: ANXA1 drives immunotherapy resistance in the infiltrated phenotype.
Fig. 6: Survival analyses across SCLC phenotypes.
Fig. 7

Data availability

The public datasets analysed during the current study are available in the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/), Cbioportal (https://www.cbioportal.org/study/summary?id=sclc_ucologne_2015), and previous relevant studies, including one published SCLC RNA-seq data from Park et al. with treatment information [17]. and one published SCLC scRNA-seq data from Chan et al. (HTAN MSK) [15]. The processed RNA-sequencing data (HMU) is provided as supplementary information in Table S1. The raw sequence data and further clinical information utilized in this analysis are immediately available from the corresponding author upon request.

Code availability

The code utilized in this analysis is available from the corresponding author upon request.

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Funding

This work was supported by grants from the Outstanding Youth Foundation of Heilongjiang Province of China (No. YQ2023H002 to L.S.Q), the National Natural Science Foundation of China (No. 62473119 to Y.X.L), the National Natural Science Foundation of China (No. 32370716 to W.Y.Z), the Heilongjiang Postdoctoral Fund (No. LBH-Z21081 to S.L.L), and Postgraduate Research & Practice Innovation Program of Harbin Medical University (YJSCX2024-24HYD to LFT). The authors thank all the participants of this work.

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Author notes

  1. These authors contributed equally: Juxuan Zhang, Yiyan Liu, Hengrui Yuan.

Authors and Affiliations

  1. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China

    Juxuan Zhang, Yiyan Liu, Hengrui Yuan, Jiaxing Deng, Lefan Tang, Xin Li, Yixin Liu, Wenyuan Zhao & Lishuang Qi

  2. Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Ning Zhan

  3. Department of Thoracic Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China

    Shilong Liu

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Contributions

LSQ and SLL were responsible for study design, data acquisition, and manuscript drafting. JXZ, YYL, and HRY performed bioinformatics analyses, including single-cell transcriptomics and high-throughput sequencing data interpretation. NZ, JXD, LFT, XL, YXL, and WYZ supervised the study, provided data curation, critical revisions, and finalised the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Shilong Liu or Lishuang Qi.

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All human samples used in this study were approved by the Ethics Committee of Harbin Medical University Cancer Hospital (ethics number: YD2025-14), and informed consent was obtained from all participants. All experiments were performed in accordance with the Declaration of Helsinki.

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Zhang, J., Liu, Y., Yuan, H. et al. Molecular phenotypes stratify small cell lung cancer for targeted therapy and immunotherapy. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03390-5

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