Tumorigenesis and Tumor Microenvironment in Lung Cancer

TL;DR

This paper explores how the tumor microenvironment influences lung cancer progression and treatment, focusing on immune cells, fibroblasts, and new therapeutic strategies.

Contribution

The paper provides a comprehensive analysis of TME dynamics in lung cancer and highlights novel therapeutic approaches targeting the microenvironment.

Findings

Chronic injury and inflammation reshape the TME to either support immunity or promote metastasis.

CAF heterogeneity and immune niche organization are critical in lung cancer progression.

Emerging therapies like immune checkpoint blockade and combined immunotherapy–radiotherapy show promise in targeting the TME.

Abstract

Lung cancer remains a leading cause of cancer mortality worldwide and continues to impose substantial clinical and economic burdens. Beyond tumor-intrinsic oncogenic drivers, disease progression and therapy response are shaped by the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, extracellular matrix, inflammatory mediators, etc. In lung cancer, chronic injury from tobacco smoke, airway disease, and treatment itself remodels local tissue programs that can either support antitumor immunity or promote immune exclusion, fibrosis, and metastatic seeding. Here, we analyze recent evidence linking lung tumorigenesis to TME ecology across histologies, with emphasis on CAF heterogeneity, spatial organization of immune niches, and the distinct microenvironments that govern organ-specific metastasis (including brain metastasis). We also evaluate emerging therapeutic strategies that aim to target or reprogram the TME, including perioperative immune checkpoint blockade, combined immunotherapy–radiotherapy approaches, and pathways such as IL-6 and TGF-β that coordinate immune suppression and stromal remodeling. Finally, we outline key gaps and potential future directions, such as longitudinal and spatial multi-omics, better biomarkers of stromal state, and trial designs that account for dynamic microenvironmental adaptation.

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