Interactions and communications in lung tumor microenvironment: Chemo/radiotherapy resistance mechanisms and therapeutic targets

The lung tumor microenvironment is composed of various cell types, including cancer cells, stromal and immune cells, as well as extracellular matrix (ECM). These cells and surrounding ECM create a stiff, hypoxic, acidic, and immunosuppressive microenvironment that can augment the resistance of lung tumors to different forms of cell death and facilitate invasion and metastasis. This environment can induce chemo/radiotherapy resistance by inducing anti-apoptosis mediators such as phosphoinositide 3-kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3), and nuclear factor of κB (NF-κB), leading to the exhaustion of antitumor immunity and further resistance to chemo/radiotherapy. In addition, lung tumor cells can resist chemo/radiotherapy by boosting multidrug resistance mechanisms and antioxidant defense systems within cancer cells and other TME components. In this review, we discuss the interactions and communications between these different components of the lung TME and also the effects of hypoxia, immune evasion, and ECM remodeling on lung cancer resistance. Finally, we review the current strategies in preclinical and clinical studies, including the inhibition of checkpoint molecules, chemoattractants, cytokines, growth factors, and immunosuppressive mediators such as programmed death 1 (PD-1), insulin-like growth factor 2 (IGF-2) for targeting the lung TME to overcome resistance to chemotherapy and radiotherapy.