Immune Escape Mechanisms in Non-Small Cell Lung Cancer: From Biological Complexity to Actionable Targets

Despite significant progress in immune checkpoint inhibitors (ICIs) and targeted therapies, non-small cell lung cancer (NSCLC) continues to be associated with high rates of primary and acquired resistance. Although PD-1/PD-L1 blockade has revolutionized treatment, its clinical development has largely followed a one-size-fits-all approach, relying on limited biomarkers such as PD-L1 expression or tumor mutational burden. It is now increasingly clear that immune escape in NSCLC is orchestrated by a multifaceted, multilayered network of both tumor-intrinsic alterations and TME (tumor microenvironment)–driven mechanisms. The challenge has been to understand and to therapeutically exploit these immune escape pathways and this knowledge is now needed so that rather than embark on empirical combinations we can advance to rational, immune-informed targeted therapies.