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Background <p>Small cell lung cancer (SCLC) remains a lethal malignancy with limited therapeutic progress, largely due to its heterogeneity and the lack of biomarkers for patient stratification. This study aims to validate the prevalent molecular subtyping system in a surgically resected cohort and elucidate the subtype-specific tumor immune microenvironment (TIME) and its clinical implications.</p> Methods <p>We retrospectively analyzed the clinical and pathological characteristics of 80 patients with surgically resected SCLC. The expression levels of Achaete-scute family BHLH transcription factor 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), as well as the immune markers CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1), were assessed in 80 pathological tissue samples using immunohistochemistry (IHC). Statistical analyses, including the chi-square test, t-test, and univariate and multivariate Cox regression, were performed to evaluate the associations between SCLC molecular subtype expression levels and patients’ clinicopathological features, immune marker profiles, and prognostic outcomes.</p> Results <p>All four molecular subtypes were successfully identified and exhibited distinct distribution patterns: ASCL1-dominant SCLC (SCLC-A, 53.8%), NEUROD1-dominant SCLC (SCLC-N, 5.0%), POU2F3-dominant SCLC (SCLC-P, 3.8%), and SCLC-triple-negative (37.5%). These subtypes were not associated with conventional clinicopathological characteristics. Each subtype displayed unique TIME features. SCLC-A correlated with an immunosuppressive microenvironment enriched in FOXP3 + regulatory T cells (Tregs) (<i>r</i> = 0.458, <i>P</i> &lt; 0.001). SCLC-triple-negative, despite showing higher PD-L1 expression, exhibited an immune-infiltrated phenotype and was positively correlated with CD8 + T cells (<i>r</i> = 0.451, <i>P</i> &lt; 0.001). In contrast, SCLC-N and SCLC-P presented an “immune-desert” phenotype. Furthermore, elevated levels of carcinoembryonic antigen (CEA) and PD-L1 were identified as independent prognostic risk factors for shorter overall survival (OS), and these molecular subtypes were significantly associated with OS (log-rank <i>P</i> = 0.043).</p> Conclusions <p>This study based on IHC detection, validated the proposed molecular subtyping classification of small cell lung cancer (SCLC) through the expression patterns of transcriptional regulators. The findings demonstrated that SCLC-A and SCLC-triple-negative were respectively associated with distinct tumor immune microenvironment (TIME) features and poorer prognostic outcomes. Furthermore, carcinoembryonic antigen (CEA) and programmed death ligand-1 (PD-L1) were identified as independent prognostic factors in surgically resected SCLC patients. These conclusions may contribute to treatment decision-making for SCLC.</p>

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Clinical and pathological characteristics, immune microenvironment, and survival analysis of molecular subtypes of surgically resected small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Juncai Tian,
  • Jiaxin He,
  • Huohuan Tian,
  • Xuewen Hou,
  • Dan Liu

摘要

Background

Small cell lung cancer (SCLC) remains a lethal malignancy with limited therapeutic progress, largely due to its heterogeneity and the lack of biomarkers for patient stratification. This study aims to validate the prevalent molecular subtyping system in a surgically resected cohort and elucidate the subtype-specific tumor immune microenvironment (TIME) and its clinical implications.

Methods

We retrospectively analyzed the clinical and pathological characteristics of 80 patients with surgically resected SCLC. The expression levels of Achaete-scute family BHLH transcription factor 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), as well as the immune markers CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1), were assessed in 80 pathological tissue samples using immunohistochemistry (IHC). Statistical analyses, including the chi-square test, t-test, and univariate and multivariate Cox regression, were performed to evaluate the associations between SCLC molecular subtype expression levels and patients’ clinicopathological features, immune marker profiles, and prognostic outcomes.

Results

All four molecular subtypes were successfully identified and exhibited distinct distribution patterns: ASCL1-dominant SCLC (SCLC-A, 53.8%), NEUROD1-dominant SCLC (SCLC-N, 5.0%), POU2F3-dominant SCLC (SCLC-P, 3.8%), and SCLC-triple-negative (37.5%). These subtypes were not associated with conventional clinicopathological characteristics. Each subtype displayed unique TIME features. SCLC-A correlated with an immunosuppressive microenvironment enriched in FOXP3 + regulatory T cells (Tregs) (r = 0.458, P < 0.001). SCLC-triple-negative, despite showing higher PD-L1 expression, exhibited an immune-infiltrated phenotype and was positively correlated with CD8 + T cells (r = 0.451, P < 0.001). In contrast, SCLC-N and SCLC-P presented an “immune-desert” phenotype. Furthermore, elevated levels of carcinoembryonic antigen (CEA) and PD-L1 were identified as independent prognostic risk factors for shorter overall survival (OS), and these molecular subtypes were significantly associated with OS (log-rank P = 0.043).

Conclusions

This study based on IHC detection, validated the proposed molecular subtyping classification of small cell lung cancer (SCLC) through the expression patterns of transcriptional regulators. The findings demonstrated that SCLC-A and SCLC-triple-negative were respectively associated with distinct tumor immune microenvironment (TIME) features and poorer prognostic outcomes. Furthermore, carcinoembryonic antigen (CEA) and programmed death ligand-1 (PD-L1) were identified as independent prognostic factors in surgically resected SCLC patients. These conclusions may contribute to treatment decision-making for SCLC.