Integrating tumor macroenvironment, microenvironment and mechanobiology with organoid and organ-on-a-chip models for lung cancer immunotherapy.

Lung cancer remains the leading cause of cancer-related mortality, and immune checkpoint inhibitors (ICIs) have revolutionized its treatment. However, immunotherapy responses vary significantly among patients, and adverse effects, such as immune-related pneumonitis, pose clinical challenges. Both the tumor macroenvironment (TMaE) and tumor microenvironment (TME) play pivotal roles in modulating immunotherapy outcomes; however, the complex crosstalk between them remains insufficiently characterized. This review discusses systemic (macroenvironmental) factors, including host metabolic status, coexisting pulmonary diseases, and baseline immune competence, alongside tumor-intrinsic (microenvironmental) determinants, such as programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and immune cell infiltration. Furthermore, we highlight the role of mechanotransduction pathways, including YAP/TAZ signaling, extracellular matrix (ECM) stiffness, and mechanical stress, in immune evasion, suggesting their potential as novel therapeutic targets. Finally, we explore emerging preclinical models simulating the TME and TMaE for immunotherapy response and safety assessment using lung cancer-derived organoids and organ-on-a-chip platforms. A deeper understanding of the interplay between TMaE and TME, combined with advanced modeling approaches, may ultimately lead to more precise and personalized immunotherapy strategies for patients with lung cancer.