Transl Lung Cancer Res. 2025 Nov 30;14(11):5181-5197. doi: 10.21037/tlcr-2025-957. Epub 2025 Nov 27.

ABSTRACT

BACKGROUND AND OBJECTIVE: Lung cancer is the leading cause of global cancer mortality. Multiple primary lung cancer (MPLC) represents a clinically challenging subtype characterized by independent tumor foci. Distinguishing MPLC from intrapulmonary metastases is crucial for prognosis and treatment. This review integrates current evidence on MPLC's etiology, molecular mechanisms, diagnosis, and management, aiming to provide a clinical reference and highlight future precision medicine directions.

METHODS: We searched PubMed/MEDLINE, Web of Science, and Google Scholar for articles published between January 2000 and September 2024. Search terms included "multiple primary lung cancer", "diagnosis", "molecular characteristics", and "treatment". The selection focused on English-language research and reviews addressing MPLC pathogenesis, diagnosis, or management.

KEY CONTENT AND FINDINGS: The review delineates the multifactorial pathogenesis of MPLC, encompassing genetic susceptibility, somatic heterogeneity, clonal evolution, and epigenetic dysregulation. It frames these mechanisms against a backdrop of "field cancerization" and dynamic tumor microenvironment interactions. The evolution of diagnosis from histology to integrated molecular-artificial intelligence (AI) models is detailed, alongside treatment strategies that must overcome the challenge of inter-lesional heterogeneity.

CONCLUSIONS: MPLC is a distinct entity arising from genetic, epigenetic, and microenvironmental interplay. Advancing its management requires multi-omics integration to decipher pathology and identify biomarkers. Future work should develop AI-enhanced diagnostics and lesion-specific treatment strategies. This review synthesizes current evidence to inform and direct future research and clinical innovation in MPLC.

PMID:41367572 | PMC:PMC12683420 | DOI:10.21037/tlcr-2025-957

Mol Cancer. 2025 Dec 2. doi: 10.1186/s12943-025-02514-4. Online ahead of print.

ABSTRACT

BACKGROUND: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

METHODS: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

RESULTS: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.

CONCLUSIONS: This multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.

PMID:41331472 | DOI:10.1186/s12943-025-02514-4