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

Cancer Lett. 2025 Oct 11;634:218076. doi: 10.1016/j.canlet.2025.218076. Online ahead of print.

ABSTRACT

The tumor microenvironment (TME) and tumor macroenvironment (TMaE) jointly shape cancer biology by linking local cellular niches with systemic host physiology. The TME provides the immediate soil for tumor initiation, progression, and therapy resistance, whereas the TMaE integrates metabolic, immune, neuroendocrine, microbial, and inflammatory signals that remodel local ecosystems. Recent advances highlight how systemic factors, including aging, energy imbalance, chronic inflammation, cachexia, and psychosocial stress, interact with extracellular matrix remodeling, vascular dynamics, and immune surveillance to influence tumor dormancy, metastatic reactivation, and therapeutic outcomes. However, the conceptual boundaries between TME and TMaE remain unclear, mechanistic insights are limited, and current models insufficiently capture local-systemic crosstalk. Future strategies integrating multi-omics, advanced imaging, and humanized models are essential to map this multidimensional interplay. A deeper understanding of TME-TMaE will be critical to refine precision oncology, advance preventive strategies, and design combinatorial therapies targeting both local and systemic cancer ecosystems. This review highlights the roles of the TME and TMaE in tumor initiation, progression, and heterogeneity, their interactions, and the clinical implications for classification, therapy, and prognosis.

PMID:41083101 | DOI:10.1016/j.canlet.2025.218076