Overcoming adaptive resistance in non-small cell lung cancer: integrating targeted therapies, immunotherapy synergy, and nanocarrier delivery.

Lung cancer is the leading cause of cancer death, characterized by high mortality rates, tumor adaptation and heterogeneity, and immune evasion mechanisms. Despite recent advancements in chemotherapy, radiation, and surgery, survival rates for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) remain low, signifying the need for new strategies and innovative treatments. This review explores the combinatorial potential of immunotherapy with direct targeting of tumor growth to address the multifaceted challenges of NSCLC. Key approaches include small-molecule inhibitors, programmed death-ligand 1 (PD-L1) inhibition, angiogenesis inhibition, and nanotechnology-based drug delivery systems. Nanocarrier systems enable coordinated drug release and pharmacological synergy, thereby ensuring effective inhibition of pathways in the tumor microenvironment (TME). Additionally, this review addresses several resistance mechanisms in the context of specific inhibitors (e.g., EGFR and ALK inhibitors). Translational insights help bridge preclinical findings to clinical applications with an emphasis on angiogenesis inhibition and personalized approaches. Ethical considerations such as consent and preclinical safety testing are emphasized to ensure the safe development of these therapies. With the new generation of genetic engineering, immunotherapy, and targeted therapies for tumor growth, this work discusses the potential to transform lung cancer treatment.