How hypoxia and mechanics drive lung cancer progression

Hypoxia and increased tissue stiffness are well established hallmarks of the lung tumor microenvironment and have each been independently implicated in promoting cancer progression, therapy resistance, and metastatic potential. Despite this recognition, how these biophysical and biochemical cues interact to jointly regulate lung cancer behavior remains poorly understood. This review synthesizes current literature examining the individual and combined roles of hypoxia and extracellular matrix (ECM) stiffness in shaping lung tumor progression and argues for the advancement of experimental models that can capture their dynamic crosstalk. We discuss the cellular and molecular mechanisms through which hypoxic signaling and matrix stiffening arise in lung tumors, including disrupted vascularization, rapid proliferation, aberrant ECM remodeling, and increased matrix deposition, and highlight how these processes converge to influence cancer cell signaling, invasion, and treatment response. In addition, we evaluate existing in vitro lung tumor microenvironment models used to study hypoxia and stiffness, with particular attention to their strengths, limitations, and capability to recapitulate combinatorial microenvironmental cues. Finally, we outline emerging strategies and design considerations for next generation model systems capable of integrating oxygen gradients with physiologically relevant mechanical properties. By emphasizing the need for combinatory approaches, this review aims to guide researchers toward more predictive in vitro platforms and to identify critical gaps that must be addressed to better understand lung cancer mechanobiology and inform future therapeutic strategies. STATEMENT OF SIGNIFICANCE: Tumor progression is strongly shaped by the physical and chemical properties of the tumor microenvironment, yet these factors are often oversimplified in experimental models. This review focuses on how ECM mechanics and oxygen availability regulate cell-matrix interactions and tumor mechanobiology in lung cancer. By highlighting current limitations within the field, this review aims to guide the development of more physiologically relevant platforms for studying lung cancer progression and therapeutic response.